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GCSs in treatment of asthma. Choice of inhaled glucocorticosteroid

Which inhaled glucocorticosteroid should be used? Four issues need consideration: systemic bioavailability, delivery device, patient acceptance, and cost.

Systemic bioavailability

Ninety percent of the inhaled dose from pressurized metered dose inhalers (MDIs) is delivered to the walls of the pharynx and only 10% reaches the sublaryngeal airways. A greater fraction of inhaled glucocorticosteroid reaches the sublaryngeal airway with some breath-activated dry powder devices, such as the Turbuhaler®. Up to 28% of the dose administered with this device can reach the sublaryngeal airway. The other widely used dry powder device, the disk-inhaler, does not share this enhanced deposition feature. The GCS deposited in the sublaryngeal respiratory tract is very well absorbed. There is minimal evidence for active biotransformation in the lung, and therefore most of the drug reaches the systemic circulation. Eighty percent of the systemic effect of these agents is via this route. The fraction deposited in the oropharynx is swallowed, and some of the swallowed fraction is absorbed into the portal circulation (Figure 1).

New inhaled glucocorticosteroids (GCSs) should be directly compared with the standard first-generation inhaled GCS, beclomethasone. Key comparative features of inhaled glucocorticosteroid are topical activity and systemic bioavailability. There are fewer data available comparing flunisolide and triamcinolone with beclomethasone than comparing budesonide. Thus, published data are insufficient to allow completely unreserved recommendation of either flunisolide or triamcinolone.

Inhaled glucocorticosteroid are variably deactivated (biotransformed) in the liver. The rate of hepatic biotransformation can be important in determining systemic activity when using high doses of inhaled GCS: on first pass, the rate of biotransformation of beclomethasone is less than that of budesonide. Furthermore, beclomethasone, but not budesonide, can have biologically active metabolites. Thus, it has been clearly shown that at higher doses (>1600 µg/d), beclomethasone has greater systemic bioavailability than budesonide. The long-term consequences of these biochemical differences remain controversial.

My review of the existing evidence suggests that no important GCS-related side effects will occur at doses between 1600 and 2000 µg/d if budesonide is used. Changes in biochemical indices of bone and adrenal function can be measured in adults at doses higher than 1600 µg, but there is still no convincing evidence of long-term clinically relevant effects on bone or the hypothalamic-pituitary-adrenal axis with doses less than 2000 µg/d. Skin becomes thinner with long-term high doses of the earlier first-generation agents. Although posterior subcapsular cataracts have been reported, they are rare in patients treated with less than 2000 µg/d of newer inhaled glucocorticosteroids. There is no evidence that lung infections or lung structural changes increase after use of inhaled glucocorticosteroid, and this reflects the rapid removal from the lung of inhaled doses. A Swedish study showed no changes in bronchial mucosal structure after 10 years’ use of inhaled GCS.

Overall, it seems prudent to use, at higher doses, inhaled GCSs with the least systemic bioavailability, ie, budesonide or fluticasone (the latter not yet routinely available in Canada). Most patients in family practice, who require lower doses, can use beclomethasone and budesonide interchangeably.

GCSs_in_treatment_of_asthma

Delivery device

A second and equally important issue in the use of inhaled GCS is the delivery device. Many patients cannot use propellant-based metered dose inhalers either because of difficulty with coordination or because, when the CFC propellant hits the soft palate and larynx, the cooling causes inspiratory arrest (gag) or because additives (emulsifiers, oleic acid) stimulate sensory receptors in the sublaryngeal airway to cause cough. Breath-activated devices do not have these problems. The Turbuhaler® has additional advantages over other dry powder breath-activated devices in that it is additive free, it is simple to use, and each device contains 200 doses. Moreover, the particles derived from this device have favourable aerodynamic properties allowing good peripheral lower respiratory tract deposition, increasing the potential for an anti-inflammatory effect.

Concern that humidity affects drug delivery is a greater issue for the water-soluble β2-agonist terbutaline than for budesonide. Problems with pressurized MDIs can also be obviated in part by using a spacer device. Spacers also can improve lower respiratory tract deposition. The incidence of oral thrush can be reduced by using a large volume spacer device, by decreasing the frequency of administration, or, best of all, by using a dry powder inhaler. Dysphonia (hoarseness) can be a problem with both pressurized metered dose inhalers and dry powder devices, but in a recent study, the frequency of dysphonia was reduced from 21 % with a pressurized metered dose inhaler to 6% with a dry powder device.

Patient acceptance

In general, there is no need to use these agents four times daily and, by decreasing frequency of administration, compliance is increased. Twice daily dosage is adequate for maintenance therapy with three daily doses during exacerbations. Taste influences acceptability, and some of the inhaled steroids have an unpleasant taste, most notably flunisolide. Throat irritation, cough, and thrush can be avoided by using a dry powder formulation or a spacer device. Patients’ concerns about “steroids” can generally be allayed by stressing the very small doses employed.

Cost

The inhaled glucocorticosteroids available in Canada are stated in the CPS to be of approximately equal efficacy on a weight basis when inhaled using a pressurized metered dose inhaler. Thus, one can compare the cost of 30 days’ treatment at 0.8 mg/d with the four available agents (Table 2), although relative costs vary according to provincial pricing polices. The two inhaled GCSs for which pharmacokinetic and safety data are least clear and generic pressurized MDI formulations of beclomethasone are the cheapest. Proprietary formulations of beclomethasone and budesonide are priced similarly. When using 400 to 800 µg/d (low doses), one should use the cheapest of the two recommended agents as long as the delivery device is manageable.

Table 2. Cost of inhaled glucocorticosteroid therapy: Prices are manufacturers’ prices in British Columbia; cost to patient will include pharmacy markup (average 10%) and a dispensingfee.
Generic Name Brand Cost/30 Days 800 µg Daily ($)
Flunisolide Bronalide, etc 17.33
Triamcinolone Azmacort, etc 17.93
Beclomethasone Generic (Kenral) 19.20
Beclomethasone Vanceril 20.52
Budesonide (turbo-inhaler), 400 µg/inhalation Pulmicort 400 31.90
Beclomethasone, 250 µg/inhalation Becloforte 34.10
Beclomethasone, 50 µg/inhalation Beclovent 36.79
Budesonide (turbo-inhaler), 200 µg/inhalation Pulmicort 200 35.46
Beclomethasone (disk-inhaler), 200 µg/inhalation Beclodisk 200 37.03
Beclomethasone (disk-inhaler), 100 µg/inhalation Beclodisk 100 55.46

The concentration in each actuation is a practical management consideration. If 1500 µg/d is required to control symptoms, 30 inhalations of a 50-µg dose of pressurized metered dose inhaler are required daily, an impractical burden for patients. Cost comparisons have become more complicated now that it has become apparent that the Turbuhaler® doubles airway deposition, and therefore recommended dosage (and cost) can, in theory, be halved. This discovery reemphasizes the need to titrate doses of inhaled glucocorticosteroid to the minimum required to control symptoms (Table 1, step 6).

It is often stated that inhaled glucocorticosteroids are overly expensive. Available data, however, indicate that the control of asthma achieved with inhaled GCS, by reducing work absences, bronchodilator use, and emergency room and hospital visits, leads to lower overall cost to the health care system. In addition, premature death is reduced by effective anti-inflammatory treatment of asthma. For example, the Saskatchewan near-death asthma study demonstrated that the risk of death was reduced by use of inhaled glucocorticosteroid. This evidence clearly justifies the cost of inhaled steroids.

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