What you need to know about inhalers and how to use them Henry Chrystyn PhD, FRPharmS and David Price MA, MRCGP, DRCOG

Transcription

1 What you need to know about inhalers and how to use them Henry Chrystyn PhD, FRPharmS and David Price MA, MRCGP, DRCOG VM The authors describe the problems that arise with metered-dose and dry-powder inhalers, and how these can be avoided by better inhalation technique and the use of MDIs that emit ultrafine particles. Figure 1. Co-ordination and using a slow inhalation can be a problem with most MDIs, which can be minimised by using an MDI that emits ultrafine particles When asthma control is not satisfactory, then the patient s compliance and their inhalation technique should be checked before changing the prescription, along with an assessment of other factors that contribute to poor asthma control. 1 Overall, compliance is not ideal, with rates of per cent reported, especially with inhaled corticosteroids. 2-4 Patient education is important and has been proven to improve compliance rates with inhaled corticosteroids. 5 It is important to ask if the patient is happy with the type of device that they are using and to check their inhalation technique. Reviews in the UK 6 and the USA 7 have concluded that there is no difference in efficacy between inhalers. However, the studies reviewed used patients that were highly trained on how to use the devices and would have been excluded if they could not use the optimal inhalation technique. Equal efficacy, therefore, only applies to those patients with a perfect inhalation technique. Metered-dose inhalers (MDIs) should be used with good co-ordination and a slow and deep Prescriber 19 June

2 inhalation step. Dry-powder inhalers (DPIs) should be inhaled as deep and hard as you can. These are generic instructions included in the inhalation technique for all inhalers. However, the correct interpretation of these is not clear because most patients inhale too fast with an MDI 8,9 and many inhale too slow with a DPI. 10 Metered-dose inhalers Reformulation using hydrofluoroalkane propellants The old chlorofluorocarbon (CFC) propellant-based MDIs were inefficient systems to deliver their dose to the lungs; nevertheless, they have proven to be highly effective. To improve lung deposition and decrease oropharyngeal impaction, spacers were introduced. Many patients had problems with the co-ordination of dose actuation and the start of their inhalation 11 and spacers also overcame this problem. Nevertheless MDIs have proven to be very effective ever since their introduction in the mid-1950s. MDIs have now been reformulated with hydrofluoroalkane (HFA) propellants, and although there a few generic beclometasone MDIs still formulated with the old CFCs, these will soon be unavailable. The changeover to bronchodilator and fluticasonecontaining MDIs was seamless, but the reformulation of beclometasone and budesonide has not been straightforward due to incompatibilities between the particles and the propellant. Due to differences in lung deposition and dose between different HFA-propellant formulations containing beclometasone, the MHRA has issued guidance that these MDIs should be prescribed by brand and not generically. Qvar The incompatibility between beclometasone particles MDI Pros Cons Qvar ultrafine particles mean: prescribed by brand name high lung deposition with need to halve the dose compared with good penetration into the conventional CFC beclometasone lower airways MDIs reduced oropharnygeal not yet licensed for children <12 years deposition minimises no dose counter need to use a spacer optimal inhalation with good co-ordination less critical than when using the traditional MDI lung deposition less affected by inhalation flow inhalation technique not critical available as a breathactuated version (Easibreathe) Clenil same dose as the traditional prescribed by brand name CFC beclometasone MDI inhalation technique with good coordination and a slow inhalation flow is required. lung deposition is low oropharnygeal deposition is high need to use a spacer no dose counter Table 1. Pros and cons of Qvar and Clenil and the HFA propellant was first solved by formulating a solution instead of the traditional suspension aerosol. This new formulation of beclometasone (Qvar) emits ultrafine particles that are much smaller than those from the traditional suspension-formulated MDIs. This approach has solved many of the problems associated with MDI use: first it was shown that Qvar provided very efficient lung deposition and much lower oropharyngeal deposition than conventional MDIs. Secondly many of the inhalationtechnique problems associated with MDI use are not as critical when using ultrafine particles. Co-ordination of dose activation and inhalation is not critical when using this product. 12 Also lung deposition is less affected by the inhalation flow. The doubling of lung deposition 12,13 coincided with clinical studies that proved that the dose of Qvar should be halved. 14 Hence 100µg of beclometasone in a Qvar MDI is equivalent to 200µg in a beclometasone CFC-formulated MDI. The better penetration of the particles emitted from Qvar throughout all the airways may be related to the improved Asthma Quality of Life associated with this product. 15 The lower oropharyngeal impaction suggests that the need to use a spacer is reduced. Clenil A different approach to the reformulation of MDIs with HFA propellants is to use Modulite technology that enables the doseemission characteristics to mimic 48 Prescriber 19 June

3 Inhalation flow dose emission from the metering cup of DPI (reservoir or a blister type) dose emission from a capsule those of the old CFC versions. Clenil uses this methodology and the dose of this product is the same as that of the beclometasone CFC MDIs. Although the dose does not have to be halved, however, this product has retained all the disadvantages of the CFC MDIs in terms of requiring good inhalation technique, low lung deposition and high oropharyngeal impaction and the hence the need to use spacers Fostair More recently a combination of beclometasone and formoterol has been introduced. This product Fostair again uses Modulite technology, but the beclometasone particles have been designed to more closely match the ultrafine particles emitted from Qvar. Studies have shown that, like Qvar, the steroid dose of this product should be halved compared to conventional beclometasone MDIs; µg of beclometasone delivered from Fostair is not equivalent to 100µg of beclometasone from Clenil. Alvesco Ciclesonide (Alvesco) is a new inhaled corticosteroid that is formulated with an HFA propellant that also emits ultrafine particles Time post start of inhalation patient s inhalation flow profile through a DPI Figure 2. Schematic design of a patient s inhalation profile through a dry-powder inhaler superimposed with the dose release from a reservoir or blister and from a capsule similar to those of Qvar. This MDI product, therefore, has a high lung deposition with low oropharyngeal impaction. Inhalation technique Patients that have problems with co-ordination should be prescribed a breath-actuated MDI, while a 2Tone Trainer has been reported to be a useful training aid to help patients use a slow inhalation. 17 When training a patient to use their MDI it should be noted that, to use a slow inhalation, a useful method to adopt is to instruct the patient to make their inspiration over five seconds. This is because the usual inhalation volume is about 2.5 litres, and if this takes five seconds then this translates into the most desirable flow of 30 litres per minute when using an MDI. If a slow inhalation is used, then coordination is not important as long as the dose is released after the patient starts to inhale. 18 When using a spacer the AeroChamber makes a noise when the inhalation rate is too fast and only has a volume of 150ml; it is therefore easily emptied during one inhalation. The advantages and disadvantages of Qvar and Clenil are presented in Table 1. Dry-powder inhalers DPIs are all breathe actuated but, like the MDI, there are many potential problems during inhalation that may affect lung deposition. DPIs are formulated either as separate single doses or multidose devices. The doses of multidose DPIs are either individually factorydispensed doses sealed onto a strip inside the device or present in a hopper (reservoir) with dose metering performed by the patient according to the manufacturer s instructions. Figure 2 shows when the dose is released from a DPI and an inhalation profile through the device. This illustrates that dose emission from DPIs formulated with either a reservoir or blister occurs immediately at the start of the inhalation, while from a capsule inhalation volume is also important because the capsule needs to be emptied. To ensure emptying of the capsule, manufacturers usually instruct patients to make two separate inhalations for each dose. Respiratory dose During inhalation the patient s inhalation flow combines with the resistance inside the device to provide a turbulent energy. 19 This energy is required to transform the metered-powder formulation into an emitted dose containing particles with the potential for lung deposition (a respirable dose). Figure 2 highlights that this has to occur immediately at the start of an inhalation, and therefore the instruction to inhale as deep and hard as you can must be from the start. If the patient gradually builds up their inhalation to a maximum flow after, for example, one second, then the initial energy may Prescriber 19 June

4 DPI Pros Cons Capsule DPIs formulation is protected from need to insert the dose before (Aerolizer and Cyclohaler moisture use note the HandiHaler is need to use two separate only licensed for COPD so inhalations for each dose is not considered here) patients need to inhale as fast as they can for as long as they can highly likely that there is dose remaining in the capsule even after the second inhalation low resistance so patients may inhale too fast resulting in high oropharyngeal impaction and low lung deposition patients have more problems using these compared to other DPIs Low-resistance DPIs easy to achieve a fast inhalation inhalation flow may be too fast (Accuhaler, Diskhaler, flow oropharyngeal deposition will Novolizer) good protection from moisture be higher and lung deposition dose counter usually lower than other DPIs inhalation flow likely to decrease if patient deteriorates Novolizer requires a minimum inhalation flow to emit a dose Medium-/high-resistance low inhalation flows reduce oro- doses stored in a reservoir inside device pharyngeal flow and increase the device so need good lung deposition. moisture protection. good distribution throughout the patients may have problems airways achieving the required minimum overall reduced inter- and intra- inhalation flow patient variability less tendency for inhalation flow to be affected when patients deteriorate dose counter Table 2. Pros and cons of different dry powder inhalers not be sufficient to create the respirable dose. Since the energy created inside a DPI to generate the respirable dose is a product of the inhalation flow and the inhaler s internal resistance, then the faster the flow then the higher will be the energy. Therefore all DPIs have flowdependent dose emission, and so the faster the inhalation flow then the better is the quality of the emitted dose. However this not clinically important because if a respirable dose is emitted, the patient s dose is titrated to their control. This issue between inhalation flow and respirable dose becomes important when the flow (and hence energy) is not sufficient to create a respirable dose with the necessary characteristics for lung deposition. Insufficient research has been devoted to this issue but it is generally accepted that the minimum flow is 30 litres per minute. However there are some DPIs with a high resistance that provide effective lung deposition below this flow. These inhalers (for example Clickhaler 20 and Easyhaler 21 ) have a high resistance so only need a low inhalation flow to achieve a set turbulent energy inside the device. Inhalation flow Another issue that has not been considered is patients inhaling too fast through a DPI with low resistance. If the inhalation is too fast there may be insufficient residence time inside the device for the formulation to be deaggregated. A fast inhalation will also provide high oropharyngeal impaction and central lung deposition rather than an even distribution throughout the airways. In contrast, a slow inhalation with effective deaggregation will decrease oropharnygeal impaction and increase lung deposition with a more even distribution throughout the airways. This would be beneficial for anti-inflammatory agents, and inhalation against a higher resistance does provide better lung deposition. 22 DPIs that have a low resistance are the Accuhaler, Aerolizer, Cyclohaler, Diskhaler, Novolizer and Spinhaler patients should be able to inhale at flows of over 60 litre per minute through these DPIs. Those with a medium/high resistance are the Clickhaler, Easyhaler, Pulvinal, Turbohaler and Twisthaler some patients may not be able to inhale at flows over 30 litres per minute. Attention should focus on the minimum energy inside the device and definition of the inhalation flow that is too fast rather than a marketing strategy that focuses on optimal/peak inhalation flow. Hence we need information about the inhalation flow window for Prescriber 19 June

5 each inhaler, then evaluate if all patients can achieve this and identify the type of patient that may not. Overall many patients can achieve 30 litres per minute through a DPI and this can be checked using the In-Check Dial. Some young children and those with severe asthma and COPD may have problems achieving this minimum flow when stable. 23 When patients deteriorate, especially during acute exacerbations, then their inhalation flow through a DPI will be slower. 24 This, therefore, could be clinically important. It has been shown that DPIs with a low resistance are more prone to this fall in the inhalation rate than those with a high resistance. 25 The minimum flow through DPIs with low resistance will be higher than 30 litres per minute. The advantages and disadvantages of different DPIs are shown in Table 2. Interchangeability Each type of inhaler has its unique design, formulation and inhalation technique, thus they should not be regarded as interchangeable. A recent study has shown that asthma control decreases and unplanned GP consultations increase when asthma patients are switched to a different device without a consultation. 26 Summary Patients have problems using all types of inhalers and so each prescribing decision has to be individualised. In general patients have problems with co-ordination and with using a slow inhalation flow with MDIs. These issues are minimised when using ultrafine particles emitted from an MDI, but this only applies to three products (Qvar, Fostair and Alvesco). DPIs all have flow-dependent dose emission and different levels of resistance. Some patients do not have sufficient inspiratory ability to use these efficiently, especially those with severe obstruction and also during an acute exacerbation. Overall those with a higher resistance are less affected by this than those with low resistance. Information about the required inhalation flow window for each DPI is required. Patients can be compliant, but if their inhalation technique is not correct then they may not receive any dose into their lungs. The inhalation technique of all patients should be checked before changing their prescription. References 1. Haughney J, et al. Respir Med 2008;102: Hoskins G, et al. Thorax 2000;55(1): Dasgupta R, et al. Pharmacoeconomics 2003;21(5); Spector S. J Asthma 2000;37(5): Onyirimba F, et al. Ann Allergy Asthma Immunol 2003;90; Brocklebank D, et al. Health Technology Assessment 2001;5(20). 7. Dolovich MB, et al. Chest 2005; 127: Reesor Nimmo CJ, et al. Ann Pharmacother 1993;27: Hesselink AE, et al. Scand J Prin Health Care 2001;9: Chrystyn H. Resp Med 2003;97: Paterson IC, et al. Br Med J 1976; 1: Leach CL, et al. Eur Respir J 1998: 12: Leach CL, et al. Chest 2002;122: Busse WW, et al. J Allergy Clin Immunol 1999;104: Juniper EF, et al. Chest 2002; 121: Fabbri LM, et al. Expert Opin Pharmacother 2008;9: Al-Showair RAM, et al. Chest 2007;131; Newman SP, et al. Eur J Respir Dis 1982;63(Suppl 119): Clark AR, et al. J Aerosol Med 1993;6: Newhouse MT, et al. Chest 1999;115: Koskela T, et al. Respir Med 2000; 94: Svartengren K, et al. Am J Respir Crit Care Med 1995;152: Chrystyn H, et al. Am J Resp Crit Care Med 2002;165(8):A Pedersen S. Arch Dis Child 1986; 61: Clark A. Respiratory Drug Delivery IV 1994; Thomas M, et al. BMC Pulmonary Medicine 2009;9:1. Professor Chrystyn is head of pharmacy at the School of Applied Sciences, University of Huddersfield, and David Price is GPIAG professor of primary care respiratory medicine in the Department of General Practice and Primary Care, University of Aberdeen Forum If you have any issues you would like to air with your colleagues or comments on articles published in Prescriber, the Editor would be pleased to receive them and, if appropriate, publish them on our Forum page. Please send your comments to: The Editor, Prescriber, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ, or to prescriber@wiley.com 52 Prescriber 19 June