천식의 초기 약물 [개요]

천식 급성 악화 증상이 있는 모든 환자들에게 즉각적인 SABA (알부테롤: 속효성 베타항진 흡입제)를 투약합니다. 천식 급성 악화 증상이 있는 환자들에서 장기간 사용하는 조절제 시작과 동시에 종종 단기간의 전신 글루코코르티코이드가 필요하기도 합니다. 조절제의 선택의 환자의 증상에 기반하며 증상 조절이 되면 단계별로 감량합니다 (stepped down).

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모든 천식 환자들은 천식 증상의 즉각적 개선을 위해 빠른 작용 시간을 나타내는 흡입 기관지 확장제를 사용해야 합니다. 전통적 선택은 short acting beta agonist (SABA)인 알부테롤 또는 lebalbuterol입니다. 알부테롤의 대표적인 상품명은 벤토린입니다.

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대안으로 저용량 gluocorticoid-formoterol inhaler (160 mcg-4.5 mcg)를 사용할 수 있으며 천식 증상 개선을 위해 1회 흡입합니다 (off-label)

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이전에 천식 치료를 받지 않았거나 단순히 SABA만 사용한 환자에서 천식 조절제 시작과 약제 선택은 환자의 천식 증상 중증도에 따라 다릅니다.

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Approaches to asthma controller therapy in adolescents and adults

National Asthma Education and Prevention Program: Expert Panel Report 3 (NAEPP-EPR 3; 2007)		Global Initiative for Asthma (GINA; 2019)
Asthma symptoms/lung function	Therapy*	Asthma symptoms	Therapy
Intermittent asthma/step 1		Step 1
Daytime symptoms ≤2 days/week Nocturnal awakenings ≤2/month Normal FEV1 Exacerbations ≤1/year	SABA, as needed	Infrequent asthma symptoms (eg, <2 times/week)	Low-dose ICS with rapid onset LABA (eg, budesonide-formoterol combination MDI 160 mcg-4.5 mcg/inhalation or DPI 200 mcg-6 mcg/inhalation) 1 inhalation, as needed or Low-dose ICS whenever SABA used
Mild persistent asthma/step 2		Step 2
Daytime symptoms >2 but <7 days/week Nocturnal awakenings 3 to 4 nights/month Minor interference with activities FEV1 within the normal range Exacerbations ≥2/year	SABA as needed for symptom relief plus Daily low dose ICS (preferred) or Daily LTRA	Asthma symptoms or need for reliever inhaler ≥2 times/week	Daily low-dose ICS, with SABA as needed or Low dose ICS-formoterol, as needed or Take ICS whenever SABA taken, as needed or (less preferred) Daily LTRA, with SABA as needed
Moderate persistent asthma/step 3		Step 3
Daily symptoms Nocturnal awakenings >1/week Daily need for SABA Some activity limitation FEV1 60 to 80% predicted Exacerbations ≥2/year	SABA as needed for symptom relief plus Daily low-dose ICS-LABA combination or Daily medium-dose ICS or Daily low-dose ICS plus LTRA	Troublesome asthma symptoms most days, nocturnal awakening due to asthma ≥1 time/month, risk factors for exacerbations¶	Low-dose ICS-LABA daily and as reliever therapy (ie, budesonide-formoterol) or Daily low-dose ICS -LABA combination, with SABA as needed or Daily medium-dose ICS, with SABA as needed or Daily low-dose ICS plus LTRA, with SABA as needed
Severe persistent asthma/steps 4 to 6		Steps 4 to 5
Symptoms all day Nocturnal awakenings nightly Need for SABA several times/day Extreme limitation in activity FEV1 <60% predicted Exacerbations ≥2/year	Step 4: Daily medium-dose ICS-LABA Possible addition of LTRA, zileuton   Step 5: Daily high-dose ICS-LABA Possible addition of omalizumab for patients with allergies   Step 6: Daily high-dose ICS-LABA May need short course of oral glucocorticoids Possible addition of omalizumab for patients with allergies	Severely uncontrolled asthma with ≥3 of the following: daytime asthma symptoms >2 times/week; nocturnal awakening due to asthma; reliever needed for symptoms >2 times/week, or activity limitation due to asthma or An acute exacerbation	SABA as needed for symptom relief and   Step 4: Daily medium-dose ICS-LABA or Daily high-dose ICS-May need short course of oral glucocorticoids Possible add-on tiotropium, LTRA ​ Step 5: Daily high-dose ICS-LABA Assess for possible add-on therapy (eg, tiotropium, zileuton, anti-IgE, anti-IL5/5R, anti-IL4R) May need short course of oral glucocorticoids

Initial therapies are noted above. A higher level of initial therapy, sometimes with concurrent use of oral glucocorticoids, may be chosen if the patient presents with an acute exacerbation. Treatment may be stepped down if asthma is well controlled for at least 3 months, or stepped up 1 or 2 steps if asthma is not well controlled or is very poorly controlled.

FEV1: forced expiratory volume in one second; SABA: short-acting beta agonist; ICS: inhaled corticosteroid (glucocorticoid); LABA: long-acting beta agonist; MDI: metered dose inhaler; DPI: dry powder inhaler; LTRA: leukotriene receptor antagonist; IgE: immunoglobulin E; IL: interleukin.

* Theophylline and cromolyn are not included in the table even though they were included in NAEPP-EPR 3 (2007). They are rarely used now, due to availability of more effective options.

¶ Risk factors for exacerbations include: smoking, allergen exposure if sensitized, previous intubation or intensive care unit stay for asthma, low FEV1 (especially <60% predicted), obesity, food allergy, chronic rhinosinusitis, and poor adherence/inhaler technique.

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GINA strategy for asthma treatment in adults and adolescents

The stepwise approach is meant to assist, not replace, the clinical decision-making required to meet individual patient needs. If alternative treatment is used and response is inadequate, change to the preferred treatment before stepping up. Refer to UpToDate content on asthma management for more information about the decision-making that supports the various treatment options.

Alphabetical order is used when more than one treatment option is listed within either preferred or alternative therapy.

ICS: inhaled corticosteroid (glucocorticoid); SABA: inhaled short-acting beta2-agonist; LTRA: leukotriene receptor antagonist; LABA: long-acting inhaled beta2-agonist; IgE: immunoglobulin E; IL-5: interleukin 5; IL-5R: interleukin 5 receptor; IL-4R: interleukin 4 receptor; OCS: oral corticosteroid (glucocorticoid); BDP: beclomethasone dipropionate; HDM: house dust mite; SLIT: sublingual immunotherapy; FEV1: forced expiratory volume in one second.

* Off-label; data only with budesonide-formoterol (bud-form).

¶ Off-label; separate or combination ICS and SABA inhalers.

Δ Consider adding HDM SLIT for sensitized patients with allergic rhinitis and FEV1 >70% predicted.

◊ Low-dose ICS-formoterol is the reliever for patients prescribed budesonide-formoterol or beclomethasone-formoterol maintenance and reliever therapy.

Reproduced with permission from: Global Initiative for Asthma. Asthma Management and Prevention (for Adults and Children Older than 5 Years): A Pocket Guide for Health Professionals, Updated 2019.

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Intermittent asthma 환자들은 전통적으로 증상 개선을 위해 필요시 SABA를 사용해 왔었습니다. 그러나 저용량 gluocorticoid-formoterol inhaler (160 mcg-4.5 mcg)를 사용하는 새로운 접근 방법이 GINA에 의해 권고되었습니다. 포모테롤은 작용시간이 빠르고 오래 지속됩니다 (~12시간). 대안으로 GINA는 증상 개선을 위해 SABA를 사용할 때마다 low-dose glucocorticoid inhaler를 사용할 것을 권고합니다. 후자를 위해서는 필요시 사용할 때마다 2개의 분리된 흡입제가 있어야 합니다.이러한 새로운 접근법은 간헐적인 천식에도 존재하는 것으로 생각되는 만성 기도 염증을 치료하고 SABA만으로 치료하는 간헐적인 천식을 가진 환자들에게서 발생할 수 있는 심각하고 잠재적으로 생명을 위협하는 천식 발작의 위험을 줄이기 위함입니다.

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천식 증상의 유발이 예견될 때 (예, 운동유발성 기관지수축) 노출 5-20분 전 SABA 또는 fast acting LABA (포모테롤)이 포함된 흡입제 그리고 글루코코르티코이드 (부데소나이드-포모테롤)로 사전 처치를 하는 것이 증상 발생을 막거나 둔하게 하기 위해 권고됩니다.

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Mild persistent asthma 환자에서 저용량 흡입 스테로이드가 포함된 치료를 권고합니다.

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Estimated comparative daily doses for inhaled glucocorticoids in adolescents and adults

Drug	Low dose	Medium dose	High dose
Beclomethasone HFA (Qvar and Qvar RediHaler products available in United States)*	80 to 160 mcg	>160 to 320 mcg	>320 mcg
40 mcg per puff	2 to 4 puffs	¶	¶
80 mcg per puff	1 to 2 puffs	3 to 4 puffs	>4 puffs
Beclomethasone HFAΔ (Qvar product available in Canada, Europe, and elsewhere)	100 to 200 mcg	>200 to 400 mcg	>400 mcg
50 mcg per puff	2 to 4 puffs	¶	¶
100 mcg per puff	1 to 2 puffs	3 to 4 puffs	>4 puffs
Budesonide DPI (Pulmicort Flexhaler product available in United States)*	180 to 360 mcg	>360 to 720 mcg	>720 mcg
90 mcg per inhalation	2 to 4 inhalations	¶	¶
180 mcg per inhalation	1 to 2 inhalations	3 to 4 inhalations	>4 inhalations
Budesonide DPIΔ (Pulmicort Turbuhaler product available in Canada, Europe, and elsewhere)	200 to 400 mcg	>400 to 800 mcg	>800 mcg
100 mcg per inhalation	2 to 4 inhalations	¶	¶
200 mcg per inhalation	1 to 2 inhalations	3 to 4 inhalations	¶
400 mcg per inhalation	1 inhalation	2 inhalations	>2 inhalations
Ciclesonide HFA (Alvesco product available in United States, Europe, and elsewhere)*	80 to 160 mcg	>160 to 320 mcg	>320 mcg
80 mcg per puff	1 to 2 puffs	3 to 4 puffs	¶
160 mcg per puff	1 puff	2 puffs	>2 puffs
Ciclesonide HFAΔ (Alvesco product available in Canada)	100 to 200 mcg	>200 to 400 mcg	>400 mcg
100 mcg per puff	1 to 2 puffs	3 to 4 puffs	¶
200 mcg per puff	1 puff	2 puffs	>2 puffs
Flunisolide MDI (Aerospan product available in United States)*	320 mcg	>320 to 640 mcg	Insufficient data
80 mcg per puff	4 puffs	5 to 8 puffs	Insufficient data
Fluticasone propionate HFA (Flovent HFA product available in United States)*	88 to 220 mcg	>220 to 440 mcg	>440 mcg
44 mcg per puff	2 to 5 puffs	¶	¶
110 mcg per puff	1 to 2 puffs	3 to 4 puffs	¶
220 mcg per puff	◊	2 puffs	>2 puffs
Fluticasone propionate HFAΔ (Flovent HFA product available in Canada, Europe, and elsewhere)	100 to 250 mcg	>250 to 500 mcg	>500 mcg
50 mcg per puff	2 to 5 puffs	¶	¶
125 mcg per puff	1 to 2 puffs	3 to 4 puffs	¶
250 mcg per puff	◊	2 puffs	>2 puffs
Fluticasone propionate DPI (Flovent Diskus product available in United States and Canada)*	100 to 250 mcg	>250 to 500 mcg	>500 mcg
50 mcg per inhalation	2 to 5 inhalations	¶	¶
100 mcg per inhalation	1 to 2 inhalations	3 to 5 inhalations	¶
250 mcg per inhalation	1 inhalation	2 inhalations	>2 inhalations
500 mcg per inhalation (strength not available in United States)	◊	1 inhalation	>1 inhalation
Fluticasone propionate DPI (Armonair Respiclick product available in United States)*	100 to 250 mcg	>250 to 500 mcg	>500 mcg
55 mcg per inhalation	2 to 4 inhalations	¶	¶
113 mcg per inhalation	1 to 2 inhalations	3 to 4 inhalations	>4 inhalations
232 mcg per inhalation	1 inhalation	2 inhalation	>2 inhalations
Fluticasone furoate DPI (Arnuity Ellipta product available in United States)* ​ NOTE: Inhaled fluticasone furoate has a greater anti-inflammatory potency per microgram than fluticasone propionate inhalers. Thus, fluticasone furoate is administered at a lower daily dose and used only once daily.	50 mcg (by use of pediatric DPI, which is off-label in adolescents and adults)	100 mcg	200 mcg
50 mcg per inhalation	1 inhalation	¶	¶
100 mcg per inhalation	◊	1 inhalation	2 inhalations
200 mcg per actuation	◊	◊	1 inhalation
Mometasone DPI§ (Asmanex Twisthaler product available in United States)*	110 to 220 mcg	>220 to 440 mcg	>440 mcg
110 mcg per inhalation	1 to 2 inhalations	¶	¶
220 mcg per inhalation	1 inhalation	2 inhalations	>2 inhalations
Mometasone HFA§ (Asmanex HFA product available in United States)*	100 to 200 mcg	>200 to 400 mcg	>400 mcg
100 mcg per actuation	1 to 2 inhalations	¶	¶
200 mcg per actuation	1 inhalation	2 inhalations	>2 inhalations
Mometasone DPIħ (Asmanex Twisthaler product available in Canada, Europe, and elsewhere)	200 mcg	>200 to 400 mcg	>400 mcg
200 mcg per inhalation	1 inhalation	2 inhalations	>2 inhalations
400 mcg per inhalation	◊	1 inhalation	>1 inhalation

The most important determinant of appropriate dosing is the clinician's judgment of the patient's response to therapy. The clinician must monitor the patient's response on several clinical parameters and adjust the dose accordingly. The stepwise approach to therapy emphasizes that once control of asthma is achieved, the dose of medication should be carefully titrated to the minimum dose required to maintain control, thus reducing the potential for adverse effects.

Depending on the specific product, total daily doses are administered once or twice daily.

Some doses are outside the approved product information recommendations.

DPI: dry powder inhaler; HFA: hydrofluoroalkane propellant metered dose inhaler.

* Doses shown and strengths (ie, mcg per puff or inhalation) are based upon product descriptions approved in the United States which may differ from how strengths are described for products available in other countries. Consult local product information before use.

¶ Select alternate preparation with higher mcg/puff to improve convenience.

Δ Products shaded in light blue color are not available in the United States but are available widely elsewhere.

◊ Select preparation with fewer mcg/puff.

§ Approved for once-daily dosing in mild asthma in some countries.

National Heart, Blood, and Lung Institute Expert Panel Report 3 (EPR 3): Guidelines for the Diagnosis and Management of Asthma; 2007. NIH Publication 08-4051 available at http://www.nhlbi.nih.gov/health-pro/guidelines/current/asthma-guidelines/full-report; updated with additional data from Global Initiative for Asthma (GINA); Global Strategy for Asthma Management and Prevention; 2017. Available at www.ginasthma.org.

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저용량 흡입 글루코코르티코이드 또는 glucocorticoid-LABA 흡입제의 규칙적인 (매일) 사용을 제안합니다. 왜냐하면 흡입 스테로이드의 규칙적인 사용은 증상의 빈도와 증상 개선을 위한 SABA 사용 횟수를 줄였고 삶의 질을 개선시켰으며 중증 악화의 빈도를 줄였기 때무입니다. GINA에서 제안한 대한 치료는 필요시 budesonide-formoterol 흡입제를 사용하는 것입니다 (off-label).

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Leukotriene modifier는 흡입 글루코코르티코이드의 회피가 필요할 때 대안입니다. 그러나 효능은 일반적으로 흡입제보다 떨어집니다. FDA는 몬테루카스트에 대해 잠재적 행동과 기분 관련 변화에 대해 box 경고를 내렸습니다.

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Long-term controller 치료를 받는 환자들은 증상 개선을 위해 필요 시와 증상 유발로 알려진 노출 이전에 SABA를 사용해야 합니다. 대안으로 low-dose glucocorticoid-formoterol 흡입제를 매일 사용하는 환자들은 증상 악화시 증상 개선을 위해 이 병합 흡입제를 1회 흡입할 수 있습니다. 이것을 SMART (Single-Inhaler for Maintenance and Reliever Therapy)라고 합니다.​

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Moderate persistent asthma 환자에서 선호되는 조절제는 저용량 흡입 스테로이드와 LABA의 병합제 또는 중등도 용량의 흡입 스테로이드입니다. 전자는 흡입 스테로이드 용량을 올리는 것보다 천식 증상을 조절하는데 더 효과적이라고 입증되었습니다.

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흡입 스테로이드에 흡입 long-acting muscarinic antagonist (LAMA; tiopropium)을 추가하는 것은 흡입 스테로이드에 LABA를 추가하는 것과 비교하여 동등하게 효과적임이 입증되었습니다. 이 선택은 LABA를 사용하기 어려운 환자 또는 제한적이라도 교감신경자극이 금기인 환자에서 적절합니다. 그러나 이러한 경우는 2개의 흡입제를 필요로 합니다.

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대안으로 전체적인 효과는 덜하지만 leukotriene modifier(montelukast, zafirlukast)를 저용량 흡입 스테로이드에 추가하는 것입니다. 테오필린은 현대 천식 치료에서 거의 사용하지 않습니다.

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Severe persistent asthma 환자에서 선호되는 조절치료는 medium (Step 4) 또는 high (Step 5) dose 흡입 스테로이드와 LABA의 병합입니다. 추가적인 치료로는 leukotriene modifier, tiotropium, biologic agent가 있습니다.

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REF. UpToDate 2021.01.10