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Respiratory Diseases
Published in Vincenzo Berghella, Maternal-Fetal Evidence Based Guidelines, 2022
Aref T. Senno, Ryan K. Brannon
Limited human data are available on the use of LTRA during pregnancy. Several small studies have not shown an increase in the rate of major malformations in offspring of women who took LTRA during pregnancy [30, 31]. Mean birth weight was lower, and risk of low birthweight and fetal distress was higher in the montelukast-exposed group, a difference that may have been related to asthma severity rather than drug effect. In nonpregnant individuals, these drugs are less effective than inhaled corticosteroids, and do not add much benefit to women already on inhaled steroids. They do not reduce the risk of exacerbation requiring systemic steroids, and are associated with modest improvement in PEF, with very modest decrease in use of rescue SABAs [32]. These drugs may be considered during pregnancy for women who had a good response to them prior to pregnancy, but they are not a preferred option when initiating therapy. Montelukast and zafirlukast are safe in pregnancy [33, 34]. Zileuton, a 5-lipoxygenase inhibitor, has been advised against in pregnancy based on animal data: Human data are lacking [19].
Information on level of drugs into breastmilk
Published in Wendy Jones, Breastfeeding and Medication, 2018
Leukotriene receptor antagonists are of benefit in exercise-induced asthma and in patients with associated rhinitis. There is little information on levels secreted into breastmilk but they are licenced for use in children. Due to the high level of plasma protein binding, levels in breastmilk are likely to be low. Levels of zafirlukast are reduced when the drug is administered with food.
Mechanisms of action
Published in Fazal-I-Akbar Danish, Ahmed Ehsan Rabbani, Pharmacology in 7 Days for Medical Students, 2018
Fazal-I-Akbar Danish, Ahmed Ehsan Rabbani
Zileuton directly inhibits the 5-lipoxygenase enzyme, thus blocking the synthesis of all leukotrienes. Zafirlukast and montelukast, on the other hand, reversibly inhibit the cysteinyl leukotriene-1 receptor, thus blocking the cysteinyl leukotrienes from exerting their physiological actions.
Metabolic activation of zolmitriptan mediated by CYP2D6
Published in Xenobiotica, 2021
Lingling Han, Yudi Jia, Yanjia Zhao, Chen Sun, Min Zhao, Ying Peng, Jiang Zheng
3-Methylindole, a part structure of ZOL, is a selectively toxicant to pulmonary tissues (Kalgutkar et al. 2005). Previous studies showed that cytochrome P450-mediated bioactivation of 3-methylindole is a key step responsible for the reported toxicity (Yan et al. 2007), and the toxicity of 3-methylindole is likely associated with the formation of reactive electrophilic intermediates that covalently modify cellular proteins (Yost 1989; Thornton-Manning et al. 1996) and nucleic acids (Regal et al. 2001). Zafirlukast, which contains a similar indole structure, is a mechanism-based inhibitor of CYP3A4, and related GSH conjugates have been detected in GSH-fortified microsomal incubations (Kassahun et al. 2005). This suggests the formation of reactive intermediate(s), which could be associated with zafirlukast-induced hepatotoxicity.
Asthma pharmacotherapy: an update on leukotriene treatments
Published in Expert Review of Respiratory Medicine, 2019
Hoang Kim Tu Trinh, So-Hee Lee, Thi Bich Tra Cao, Hae-Sim Park
The IC50 concentrations of zafirlukast to antagonize CysLTR1 and PGE2 are similar to those of montelukast [12,24]. The addition of high-dose zafirlukast (80 mg twice daily) to high- dose ICS was beneficial for patients with severe asthma [25]. In addition to antiasthmatic effects, zafirlukast is suggested to protect against cardiovascular disease through modulating soluble epoxide hydrolases and peroxisome proliferator-activated receptors [26]. Interestingly, zafirlukast suppresses advanced glycation end-products (AGEs)-induced degradation of extracellular matrix as well as reactive oxygen species (ROS) in chondrocytes [27]. To date, associations of the AGEs/ROS pathway with asthma pathogenesis remain to be clarified. Exploration of the antagonizing potency of zarfilukast in the AGEs/ROS pathway may help find novel therapeutic effects of LTRA in asthmatics.
Pharmacotherapeutic management of asthma in pregnancy and the effect of sex hormones
Published in Expert Opinion on Pharmacotherapy, 2021
Ruth P Cusack, Gail M Gauvreau
Cysteinyl leukotrienes are lipid mediators produced and released from eosinophils, basophils, and mast cells. These pro-inflammatory mediators released in the airways result in bronchoconstriction, mucus secretion, and smooth muscle hypertrophy. Zafirlukast and montelukast and both selective cysteinyl leukotriene receptor antagonists (LTRAs) are indicated as a maintenance controller therapy for asthma. While data for the use of both agents are limited in pregnancy, montelukast is the first line LTRA therapy for pregnancy as it has been studied most extensively. Zileuton is a leukotriene synthesis inhibitor which is not recommended in pregnancy due to fetal abnormalities in animal studies [85] with no safety evidence in human pregnancy.