This drug is used clinically every day, and many guidelines have "refused to recommend"

"Of the COPD and asthma patients I come into contact with, it can be said that six out of ten people will use this medicine." "It is estimated that 99% of the acute severe asthma patients hospitalized in our hospital will have this drug in their prescriptions."

This drug, which is commonly mentioned in the mouths of doctors, is the basic drug used to treat airway diseases - theophylline.

Theophylline, one of the commonly used drugs in respiratory medicine, has been widely used in clinical practice as a "bronchodilator" for more than 80 years. Because of its low price and easy availability, it remains one of the most widely prescribed drugs worldwide for the treatment of asthma and chronic obstructive pulmonary disease (COPD) [1].

However, in recent years, theophylline drugs have been "cold" by many guidelines due to adverse drug reactions and reduced to alternative drugs. Some doctors even said, "Hasn't this drug (aminophylline) been eliminated in the clinic?"

It is widely used clinically, but the treatment window is narrow

Theophylline (1,3-dimethylxanthine), first extracted from tea in 1895 and chemically synthesized. At the beginning of its introduction, theophylline was used as a diuretic, and its role in bronchiectasis was first reported until 1922 [2], and it was widely used in clinical practice in the 2030s.

The main role of theophylline is to expand bronchial smooth muscle, which increases intracellular cAMP levels of bronchial smooth muscle by inhibiting phosphodiesterase enzymes. However, theophylline does not significantly inhibit enzyme activity in the effective blood concentration range in vivo, so recent studies have also believed that the bronchodilating effect of theophylline is partly due to the release of endogenous epinephrine and norepinephrine.

In addition, as a purine receptor blocker, theophylline can also fight adenine and other contractile effects on the respiratory tract, enhance diaphragm contractility, reduce respiratory tract obstruction, and respiratory muscle fatigue caused by increased respiratory load.

"In addition, the drug itself is relatively cheap, and it is easy to obtain both tertiary hospitals and primary hospitals, so there are more scenarios in clinical application." Wang Kui, a doctor from the Department of Respiratory Medicine of a hospital in Wuhu City, introduced.

Theophylline drugs have a variety of derivatives, and aminophylline, diprophylline, doxofylline and so on are commonly used clinically. Among them, the average daily cost (DDDc) of oral aminophylline tablets can be as low as 0.09~0.15 yuan, and the average daily cost of oral doxofylline can be 2.74~3.40 yuan [3].

In the past few decades, with the deepening of the study of the mechanism of action of drugs, the functions of theophylline have gradually been extended: anti-inflammatory, cardiotonic, diuretic, stimulating the respiratory center and respiratory muscles, dilating coronary arteries... It is also more and more widely used in clinical practice. For example, in previous treatments, theophylline may be used for acute heart failure in addition to asthma and COPD [4].

Theophylline drugs for the treatment of acute heart failure Source: Internal Medicine (9th Edition)

But at the same time, the "fatal" shortcomings of theophylline are gradually emerging.

It is generally believed that the effective plasma concentration of theophylline is 5~15μg/ml. When the plasma concentration was greater than 15 μg/ml, the incidence of adverse reactions was significantly increased, including cardiovascular, gastrointestinal and neurological reactions; When the blood concentration is greater than 20μg/ml, it is easy to cause poisoning reactions, and even death in severe cases.

Adverse Effects and Mechanisms of Theophylline (Compiled from Goodman Gilman: Pharmacological Foundations of Therapeutics (12th Edition))

In 2018, the National Poison Data System Annual Report of the American Association of Poison Control Centers documented 88 single exposures to aminophylline or theophylline, of which 8 of the 46 patients treated in health care settings exposed to these drugs reported serious adverse outcomes and 1 death [5].

Several guidelines are no longer recommended

In recent years, theophylline has significantly declined in international guidelines. In the 2023 Global Initiative for Chronic Obstructive Lung Disease (GOLD) management guidelines, theophylline is recommended as a bronchodilator only when inhaled long-acting bronchodilators are unavailable or unaffordable. In addition, methylxanthines are not recommended for the management of COPD during acute exacerbations.

Source: GOLD 2023 [6]

A study published in JAMA looked at the effectiveness of adding low-dose theophylline to patients at high risk of COPD exacerbations treated with ICS. The results showed that the addition of low-dose theophylline did not significantly reduce the mean number of exacerbations (2.24 versus 2.23) over a one-year period compared with placebo [7]. At the same time, the TASCS study also showed that low-dose theophylline with or without prednisone did not reduce COPD exacerbations or other secondary endpoints compared with placebo [8].

In addition, in the Global Initiative for Asthma (GINA) report, aminophylline in the acute exacerbation period has long been discouraged.

Source: GINA 2023 [9]

With the update of guidelines and research evidence, many doctors have also reduced the use of theophylline drugs in the clinic. In a Danish study of theophylline use in adults, theophylline prescriptions are decreasing year by year, from 401 per 100,000 in 1997 to 26 per 100,000 in 2016 [10].

"The main reason is that the treatment window of theophylline drugs is too narrow, in layman's terms, that is, a slightly higher concentration will lead to many adverse reactions, and the concentration is low and has no therapeutic effect." Shen Ling, chief physician of the Department of Respiratory and Critical Care of Hangzhou First People's Hospital affiliated to Zhejiang University School of Medicine, said that he has basically not used theophylline drugs now.

"In theory, the use of this drug requires blood concentration monitoring, but in practice, few hospitals have the conditions or energy to do this."

In addition, it is more common in clinical practice to use the irrational combination of theophylline drugs. Theophylline can react with antibacterial drugs, verapamil, cimetidine and other drugs, affecting theophylline clearance, resulting in an increase or decrease in the concentration of theophylline in the blood.

Factors affecting serum theophylline concentration Source: Clinical Therapeutics (8th Edition)

A tertiary hospital in southwest China reported a case of adverse reactions caused by aminophylline combined with quinolones: an elderly patient was treated in an external hospital due to acute exacerbation of COPD, and moxifloxacin, clindamycin and levofloxacin were successively used for anti-infective treatment, during which intravenous infusion of aminophylline. Although the patient was always at a normal dose of aminophylline, theophylline poisoning such as limb tremor had occurred on admission. After monitoring, the plasma concentration of theophylline reached 26 micrograms/ml, and the symptoms improved after stopping the drug [11].

Doctor: Attention should be paid to before and after medication

In fact, with the continuous update and iteration of inhaled drugs such as beta2 receptor stimulants and hormones, theophylline has long been not a first-line recommendation in the guidelines. The Guidelines for the Prevention and Treatment of Bronchial Asthma (2020 Edition) mention that as an alternative control agent, sustained-release theophylline maintenance therapy can be added to patients with asthma that remains uncontrolled by inhaled ICS or ICS+LABA.

Theophylline drugs are still "active" in the clinic, and there are multiple practical factors.

Source: Lilac Garden comment area

On the one hand, cheap and easy availability are favorable factors for the initial clinical spread of theophylline. Theophylline and aminophylline are both listed in the "National Essential Medicines List of China", and the reimbursement ratio in medical insurance will be significantly higher than that of non-essential drugs, and the allocation ratio of corresponding medical institutions is also clearly required.

On the other hand, according to the "China Adult Lung Health Study" [12-13], there are more than 100 million COPD patients in mainland China; The prevalence of asthma in people aged 20 years and older is 4.2%, with a total of 45.7 million patients, of whom 26.2% have airway limitation of pulmonary function. Respiratory diseases are mostly elderly patients, and the burden of treatment and management mostly falls on grassroots hospitals.

Therefore, although the recommended medication for asthma and COPD has gradually changed to inhalation in the continental guidelines, the overall level of medication is still unbalanced, and the implementation effect of the guidelines is not satisfactory.

An analysis of asthmatic drugs in a community health service center in Shanghai showed that the proportion of theophylline drug use cases could be as high as 77.40%. In terms of results, this is seriously inconsistent with the guidelines for diagnosis and treatment, but in fact, only 4 patients were able to take care of themselves and were able to use inhalants [14].

"In my opinion, medication is also a case-by-case and specific analysis." Zhang Jun, a respiratory physician at the Affiliated Hospital of Ningbo University School of Medicine, said, "For example, most of the patients we contact in our hospital are critically ill, and the situation is complicated, and they are usually combined drugs."

"In addition, the doxofylline used in our hospital is cheap and does not have much side effects when observed, and critically ill patients also have to monitor heart rate frequently with ECG monitoring, so the overall adverse reactions are relatively few." But if it's in a stable phase, the treatment plan will definitely be different."

In the view of Zhang Kui, a respiratory doctor at another hospital, the adverse reactions of theophylline drugs are clear, but its efficacy is also undoubted. "In addition to post-medication observation, perhaps more important is the judgment before medication. For example, whether patients have already used some drugs that will affect the metabolism of theophylline, and patients with poor heart function and elderly patients, in the face of these special groups, they may need more attention when taking drugs."

Acknowledgements: This article has been professionally reviewed by Shen Ling, chief physician of the Department of Respiratory and Critical Care Medicine, Hangzhou First People's Hospital affiliated to Zhejiang University School of Medicine, and Deng Yanhui, deputy chief pharmacist of the Third Affiliated Hospital of Southern Medical University

The author of this article: to crisp

Curated by: ame | Executive Producer: Gyouza

Source: Visual China

Resources:

[1]https://doi.org/10.1164/rccm.201302-0388PP

[2]doi/10.1111/j.1365-2222.1982.tb01641.x

[3] HE Zhi,HAN Yu.Analysis of theophylline drug use in a tertiary general hospital from 2009 to 2017[J].China Hospital Statistics,2020,27(1):40-42.DOI:10.3969/j.issn.1006-5253.2020.01.007.

[4] ZHANG Xinchao, DENG Ying, SHANG Deya. Chinese emergency management guidelines for acute heart failure(2022)[J].Chinese Journal of Emergency Medicine,2022,31(8):1016-1041.)

[5] Gummin DD, Mowry JB, Spyker DA, Brooks DE, Beuhler MC, Rivers LJ, et al. 2018 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 36th Annual Report. Clin Toxicol (Phila). 2019 Dec. 57 (12):1220-1413.

[6]https://goldcopd.org/2023-gold-report-2/

[7] Devereux G, Cotton S, Fielding S, et al. Effect of Theophylline as Adjunct to Inhaled Corticosteroids on Exacerbations in Patients With COPD: A Randomized Clinical Trial. JAMA 2018; 320(15): 1548-59.

[8] Jenkins CR, Wen FQ, Martin A, et al. The effect of low-dose corticosteroids and theophylline on the risk of acute exacerbations of COPD: the TASCS randomised controlled trial. Eur Respir J 2021; 57(6).

[9]https://ginasthma.org/2023-gina-main-report/

[10] Henriksen DP, Davidsen JR, Laursen CB. Nationwide use of theophylline among adults-A 20-year Danish drug utilisation study. Respir Med. 2018;140:57-62. doi:10.1016/j.rmed.2018.05.015

[11] Ao Man, Lu Lei, Xiong Yi. A case report of muscle tremor caused by the application of aminophylline combined with antibacterial drugs[J].Modern Medicine and Health,2017,33(6):955-956.)

[12] Wang C, Xu J, Yang L, et al. Prevalence and risk factors of chronic obstructive pulmonary disease in China (the China Pulmonary Health [CPH] study): a national cross-sectional study. Lancet. 2018;391(10131):1706-1717. doi:10.1016/S0140-6736(18)30841-9

[13] Huang K, Yang T, Xu J, et al. Prevalence, risk factors, and management of asthma in China: a national cross-sectional study [J]. Lancet, 2019, 394(10196):407-418. DOI:10.1016/S0140-6736(19)31147-X.

[14] JI Qi. Analysis of antiasthmatic drugs in inpatients in community health service centers[J].Shanghai Medicine,2016,37(18):23-25.)