Bosentan


Article Author:
Omar Masarweh


Article Editor:
Abhishek Bhardwaj


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
5/12/2019 3:04:10 PM

Indications

Bosentan is FDA approved for the treatment of patients with pulmonary arterial hypertension (PAH) with significant physical limitations to increase their exercise ability and decrease the rate of clinical worsening.[1][2][3] There are several non-FDA approved uses of bosentan for the treatment of idiopathic or congenital PAH in the pediatric population ages 3 years and older.[4] New studies have shown that it may be useful in the treatment of chronic thromboembolic pulmonary hypertension (CTEPH). Clinical trials in the use of endothelial receptor antagonists, such as bosentan, for the treatment of Eisenmenger syndrome, have shown some promise, with further research needs to be conducted to investigate its safety profile and efficacy.[5] Furthermore, non-FDA approved uses of bosentan include adjunct therapy for thromboangiitis obliterans, also known as Buerger disease.[6]

Mechanism of Action

Endothelins consist of a group of 21 amino acid peptides with three different isoforms, ET-1, ET-2, and ET-3, with ET-1 being the most abundant and found in sites such as the airway epithelium, parenchymal cells of the lung, pulmonary tumors, pulmonary vasculature, kidneys, small intestine, and cardiac myocytes.[7] Once produced and secreted, endothelins bind to endothelin G protein-coupled receptors of which two primary forms exist, endothelin A and endothelin B (ETA and ETB, respectively).  Although these receptors are present throughout the lung tissue, ETA receptors have their highest concentrations in the pulmonary vasculature and airway smooth muscle, whereas ETB receptors are most abundantly present in the endothelium.[8] The binding of endothelin to the ETA receptors causes vasoconstriction, while binding to the ETB receptors causes bronchoconstriction. Due to the location and function of endothelins, implications point to them in many respiratory diseases such as asthma, pulmonary hypertension, COPD, connective tissue diseases, bronchiolitis obliterans, and lung transplant rejection. The intended role of bosentan is to antagonize these receptors in lung tissue causing the smooth muscle along the pulmonary vasculature to relax, decreasing pulmonary pressures and resistance. In clinical studies, bosentan proved to prevent ET-1 mediated cellular proliferation.[8]

One consequence of antagonizing the ETB receptors results in a relative increase in the amount of circulating ET-1.[8][7]

Administration

Bosentan is administered orally as a film-coated tablet or as an oral suspension. When used in the treatment of pulmonary artery hypertension, bosentan is given twice daily at either 125mg or 250mg doses for adults. In the pediatric population, patients less than 12 years old bosentan dosage ranges from 31.25mg-125mg twice daily.[8]

Adverse Effects

In clinical trials with bosentan for the treatment of pulmonary artery hypertension, the most common adverse effects included headache (22%), flushing (9%), syncope (7%) and hepatic dysfunction (8%). In these clinical trials, less common adverse effects included cough, dyspnea, respiratory tract infections, chest pain, hypotension, sinusitis, dizziness, and in some cases worsening of PAH.[8] According to the FDA labeling of bosentan, embryo-fetal toxicity occurred in animal studies, and therefore pregnancy testing should be conducted on any female of reproductive age or any female that thinks she could be pregnant. Other less common adverse effects include fluid retention which may lead to hospitalization of patients with preexisting heart failure.[8] Additional, less common adverse effects observed included a transient decrease in sperm count and decreases in hemoglobin and hematocrit.[8]

Contraindications

Contraindications to bosentan include females who are or may become pregnant due to the risk of embryo-fetal toxicity. Due to the high risk, any female who is eligible for bosentan must be on two or more forms of reliable contraception during treatment, as well as for one month following completion of treatment.[8] Additional contraindications include using bosentan while taking cyclosporin A. Clinical studies have shown concomitant use of bosentan and cyclosporin A has resulted in drastic increases in the plasma level of bosentan increasing the risk for adverse effects and toxicity. Further contraindication includes the use of bosentan in patients taking glyburide due to the increased risk of hepatotoxicity resulting in increased levels of liver enzymes.[8]  Finally, anyone allergic to bosentan or any of its parts should not take bosentan due to the risk of hypersensitivity reactions resulting in DRESS syndrome, anaphylaxis, rash, and angioedema.[8]

Monitoring

When given at therapeutic doses, bosentan levels reach steady-state after 3 to 5 days of therapy. The hepatic cytochrome P450 enzyme system metabolizes bosentan into two active metabolites. Only one of the metabolites (Ro 48-5033) can exert effects similar to bosentan, however with only less than 20% of the effect.[7] Due to the hepatic clearance of the drug and interaction with the cytochrome P450 system, bosentan is contraindicated with any CYP2C9 and 3A4 substrates, inducers, or inhibitors, in addition to glyburide and cyclosporine. Other drug-drug interactions that may require careful monitoring due to bosentan ability to increase drug metabolism by the cytochrome P450 system include protease inhibitors, certain azole antifungals, erythromycin, and amiodarone.[8] One crucial drug-drug interaction occurs with warfarin. In one clinical trial, co-administration of bosentan and warfarin resulted in a significant decrease in warfarin’s anticoagulation effects; therefore careful INR monitoring may be necessary.

Due to bosentan’s embryo-fetal toxicity, female patients must be on more than one form of contraception before starting therapy, and for one month following termination of therapy.[8]

Toxicity

Bosentan is well tolerated and when patients receive appropriate monitoring presents a very low risk for toxicity. However, when given with cyclosporin A, bosentan’s plasma levels increased 30-fold and resulted in severe headaches, nausea, and vomiting.[8] However, no serious adverse effects of toxicity presented. In one postmarket period, one episode of overdose by a male patient who took 10000mg of bosentan resulted in nausea, vomiting, hypotension, blurred vision and sweating. The patient was able to make a full recovery following adequate blood pressure support.[8]

Enhancing Healthcare Team Outcomes

Before bosentan’s emergence as a treatment for pulmonary arterial hypertension, the only other available treatments were intravenous medications, such as epoprostenol. Bosentan since has become first-line therapy for patients with pulmonary artery hypertension and has been shown in clinical trials to be effective as monotherapy, or more widely used as part of combination therapy. Due to its relative low possibility of toxicity, ease of administration, effectiveness and its disease-modifying abilities, bosentan remains as one of the go-to medications when treating patients with pulmonary artery hypertension. Continued research is needed to understand which combination therapy proves to have the best outcomes while maintaining little to no toxicity.[8]

When using bosentan for pulmonary arterial hypertension, it is best to employ an interprofessional team approach, with physicians, specialists, specialty-trained nursing staff, and pharmacists, all collaborating across disciplines to guide cases to optimal outcomes. [Level V]


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Bosentan - Questions

Take a quiz of the questions on this article.

Take Quiz
What molecule does bosentan mimic?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 60-year-old male complains of shortness of breath while doing minimal yard work. He has little information about his condition from his previous visit with his pulmonologist from a different state. He states he recently had a test that showed a right ventricular systolic pressure of 45 mmHg and his mean pulmonary artery pressure was 58 mmHg. His current medications include warfarin and a diuretic. What is the mechanism of action of the drug that would most likely be recommended?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 32-year-old G3P0 female with pulmonary arterial hypertension (PAH) presents to the office with worsening of symptoms and decreased exercise intolerance. She is currently married and uses condoms as protection with her husband. Urinary beta-hCG is negative. Which of the following should be advised to this patient before starting her on bosentan?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 65-year-old male with a past medical history positive for type 2 diabetes, hyperlipidemia, and bipolar disorder arrives at the clinic complaining of shortness of breath. After careful evaluation and diagnostic testing, the patient is found to have pulmonary artery hypertension. The provider wants to put him on a medication that would antagonize endothelin-1. Which of the following mechanisms of action of a possible preexisting medications the patient is already taking would be contraindicated if the physician prescribes this new medication to treat his pulmonary artery hypertension?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Bosentan - References

References

Pedersen J,Hedegaard ER,Simonsen U,Krüger M,Infanger M,Grimm D, Current and Future Treatments for Persistent Pulmonary Hypertension in the Newborn. Basic     [PubMed]
Elshafay A,Truong DH,AboElnas MM,Idrees H,Metwali HG,Vuong NL,Saad OA,Hirayama K,Huy NT, The Effect of Endothelin Receptor Antagonists in Patients with Eisenmenger Syndrome: A Systematic Review. American journal of cardiovascular drugs : drugs, devices, and other interventions. 2018 Apr;     [PubMed]
Narváez J,García-Gómez C,Álvarez L,Santo P,Aparicio M,Pascual M,López de Recalde M,Borrell H,Nolla JM, Efficacy of bosentan in patients with refractory thromboangiitis obliterans (Buerger disease): A case series and review of the literature. Medicine. 2016 Nov;     [PubMed]
Chen X,Zhai Z,Huang K,Xie W,Wan J,Wang C, Bosentan therapy for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: A systemic review and meta-analysis. The clinical respiratory journal. 2018 Jun;     [PubMed]
Mathier MA,Ishizawar D, Bosentan. Expert opinion on pharmacotherapy. 2010 Apr;     [PubMed]
Daizadeh I, Pulmonary Arterial Hypertension: A Case Study in FDA Expedited Program Designations. Therapeutic innovation     [PubMed]
Oldfield V,Lyseng-Williamson KA, Bosentan: a review of its use in pulmonary arterial hypertension and systemic sclerosis. American journal of cardiovascular drugs : drugs, devices, and other interventions. 2006;     [PubMed]
Boss C,Bolli MH,Gatfield J, From bosentan (Tracleer®) to macitentan (Opsumit®): The medicinal chemistry perspective. Bioorganic     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of PA-Hospital Medicine. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for PA-Hospital Medicine, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in PA-Hospital Medicine, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of PA-Hospital Medicine. When it is time for the PA-Hospital Medicine board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study PA-Hospital Medicine.