Gulliver Tanya, Morton Ronald, Eid Nemr
John Hunter Children's Hospital, Newcastle, New South Wales, Australia.
Paediatr Drugs. 2007;9(3):185-94. doi: 10.2165/00148581-200709030-00007.
The role of inhaled corticosteroids (ICS) in the treatment of childhood asthma has been well established. An ideal corticosteroid should demonstrate high pulmonary deposition and residency time, in addition to a low systemic bioavailability and rapid systemic clearance. The lung depositions of the ICS have been compared, with beclomethasone (beclometasone)-hydrofluoroalkane (HFA) and ciclesonide showing the highest lung deposition. Lung deposition is influenced by not only the inhalation device and type of propellant (HFA or chlorofluorocarbon), but also by whether the aerosol is a solution or suspension, and the particle size of the respirable fraction. Pulmonary residency time increases when budesonide and des-ciclesonide undergo reversible fatty acid esterification. The bioavailability of the drug depends on the oral bioavailable fraction and the amount absorbed directly from the pulmonary vasculature. The clearance rate of des-ciclesonide is very high (228 L/h), increasing its safety profile by utilizing extra-hepatic clearance mechanisms. Both des-ciclesonide and mometasone have a high protein binding fraction (98-99%). The volume of distribution (Vd) is proportional to the lipophilicity of the drug, with the Vd of fluticasone being 332L compared with 183L for budesonide. Increasing the Vd will also increase the elimination half-life of a drug. The pharmacodynamics of ICS depend on both the receptor binding affinity and the dose-response curve. Among the ICS, fluticasone and mometasone have the highest receptor binding affinity (1800 and 2200, respectively), followed by budesonide at 935 (relative to dexamethasone = 100). Compared with other nonsteroid asthma medications (long-acting beta-agonists, theophylline, and montelukast) ICS have proven superiority in improving lung function, symptom-free days, and inflammatory markers. One study suggests that early intervention with ICS reduces the loss in lung function (forced expiratory volume in 1 second) over 3 years. Whether airway remodeling is reduced or prevented in the long term is unknown. Potential adverse drug effects of ICS include adrenal and growth suppression. While in low-to-medium doses ICS have shown little suppression of the adrenal pituitary axis, in high doses the potential for significant adrenal suppression and adrenal crisis exists. Several longitudinal studies evaluating the effect of ICS on growth have shown a small decrement in growth velocity (approximate 1-2 cm) during the first year of treatment. However, when investigators followed children treated with budesonide for up to 10 years, no change in target adult height was noted. In conclusion, the development of optimal delivery devices for young children, as well as optimizing favorable pharmacokinetic properties of ICS should be priorities for future childhood asthma management.
吸入性糖皮质激素（ICS）在儿童哮喘治疗中的作用已得到充分确立。理想的糖皮质激素除了应具有低全身生物利用度和快速的全身清除率外，还应表现出高肺部沉积率和驻留时间。已对ICS的肺部沉积情况进行了比较，其中倍氯米松-氢氟烷烃（HFA）和环索奈德的肺部沉积率最高。肺部沉积不仅受吸入装置和推进剂类型（HFA或氯氟烃）的影响，还受气雾剂是溶液还是混悬液以及可吸入部分的颗粒大小的影响。当布地奈德和去环索奈德进行可逆的脂肪酸酯化时，肺部驻留时间会增加。药物的生物利用度取决于口服生物利用分数和直接从肺血管系统吸收的量。去环索奈德的清除率非常高（228L/h），通过利用肝外清除机制提高了其安全性。去环索奈德和莫米松都有很高的蛋白结合分数（98 - 99%）。分布容积（Vd）与药物的亲脂性成正比，氟替卡松的Vd为332L，而布地奈德为183L。增加Vd也会增加药物的消除半衰期。ICS的药效学取决于受体结合亲和力和剂量反应曲线。在ICS中，氟替卡松和莫米松具有最高的受体结合亲和力（分别为1800和2200），其次是布地奈德，为935（相对于地塞米松 = 100）。与其他非甾体类哮喘药物（长效β受体激动剂、茶碱和孟鲁司特）相比，ICS在改善肺功能、无症状天数和炎症标志物方面已被证明具有优越性。一项研究表明，早期使用ICS可减少3年内肺功能（一秒用力呼气量）的损失。从长期来看，气道重塑是否会减少或预防尚不清楚。ICS的潜在药物不良反应包括肾上腺抑制和生长抑制。虽然中低剂量的ICS对肾上腺垂体轴的抑制作用较小，但高剂量时存在显著肾上腺抑制和肾上腺危象的可能性。几项评估ICS对生长影响的纵向研究表明，在治疗的第一年生长速度会有小幅下降（约1 - 2厘米）。然而，当研究人员对接受布地奈德治疗长达10年的儿童进行随访时，未发现目标成人身高有变化。总之，开发适合幼儿的最佳给药装置以及优化ICS良好的药代动力学特性应是未来儿童哮喘管理的重点。
