Azilsartan


Article Author:
Maiah Hardin


Article Editor:
Tibb Jacobs


Editors In Chief:
Jasleen Jhajj
Cliff Caudill
Evan Kaufman


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes
Kavin Sugumar


Updated:
5/17/2019 3:23:05 PM

Indications

Azilsartan, commercially formulated as azilsartan medoxomil, is an angiotensin-receptor blocking (ARB) agent. The drug is also commercially available as a combination therapy with chlorthalidone. Azilsartan received FDA approval in 2011 as an antihypertensive agent.[1] It can be used for antihypertensive treatment as monotherapy or combination therapy with other blood pressure-lowering agents in patients 18 years of age or older.[1] According to the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults,[2] ARBs such as azilsartan are recommended as first-line agents when initiating antihypertensive therapy. ARBs are considered equally efficacious as angiotensin-converting enzyme (ACE) inhibitors, which are also first-line antihypertensive agents along with thiazide diuretics and calcium-channel blockers.[2]

In preclinical and clinical studies, azilsartan has been shown to reduce blood pressure levels more dramatically than its precursors valsartan and olmesartan and is theorized to lower mortality rates and the onset of cardiovascular disease.[3][4] The mortality benefits could be especially pertinent in patients that have had a myocardial infarction and have heart failure and may have potential off-label uses for these patients.[4]

In patients with diabetes mellitus and hypertension, ARBs are effective in reducing blood pressure in addition to the other first-line agents.[2] ACE inhibitors and ARBs are considered to be the most efficacious in decreasing the progression of moderate-to-severe albuminuria and may be used in an off-label fashion.[2] Using ARBs to treat hypertension has also been proven to prevent the recurrence of atrial fibrillation, as the two conditions are often coexistent.[2]

Mechanism of Action

ARB drugs target one of the key elements of the renin-angiotensin-aldosterone system (RAAS). In the progression of the RAAS, angiotensin II binds to AT1 receptors, which are highly expressed in vascular tissues and adrenal gland, causing significant vasoconstriction.[5][6] In addition to promoting vasoconstriction, angiotensin II binding to AT1 receptors promotes sodium and water retention and also inhibits further secretion of renin.[5] Vasoconstriction plays a significant role in increasing vascular resistance, and combined with the previously mentioned fluid retention, ultimately leads to increased blood pressure.[5] ARBs such as azilsartan selectively bind to AT1 receptors and directly prevent the actions of angiotensin II on these receptors. 

In addition to binding to AT1 receptors, angiotensin II binds to angiotensin II type 2 (AT2) receptors. The action of angiotensin II bound to AT2 receptors produces effects opposite of AT1 receptors, such as natriuresis, blood pressure lowering, and reduction of vasoconstriction in the vasculature.[5] As previously stated, azilsartan is highly selective for AT1 receptors and is not involved in the blockade of AT2 receptors.[6]

ARB drugs, such as azilsartan, provide an alternate and a highly effective option in the treatment of blood pressure involving the RAAS pathway. Many first-line options for antihypertensive treatment include ACE inhibitors, which come with associated side effects related to the ACE drug target (a dry cough, angioedema).[4] Azilsartan’s action of blocking angiotensin II from binding to the AT1 receptor does not interfere with the action of ACE, so these side effects occur much less frequently.

Administration

Azilsartan comes in an oral tablet form as 40 and 80 mg tablets that are commercially available to be taken once daily, and it can be administered with or without food.[1] Although 80 mg is the recommended starting dose for hypertensive patients, 40 mg may need to be the beginning dose for patients with concomitant high-dose diuretic therapy, as well as patients that are volume- or salt-deprived.[1] For patients with renal or mild-to-moderate hepatic impairment, dose adjustments are unnecessary; the same applies to elderly patients.[1]

Azilsartan is formulated as its prodrug, azilsartan medoxomil. It absorbs rapidly in the gut, and biotransformation in the liver leads to the prodrug being hydrolyzed to its active metabolite, azilsartan, primarily by the enzyme CYP2C9.[1] It is 60% bioavailable, with an elimination half-life of about 11 hours.[1] The time to peak concentrations in the plasma ranges between 1.5 to 3 hours and reaches steady-state concentrations after five days.[1] Azilsartan is excreted primarily in the feces (55%), and 42% gets excreted in urine; 15% of the azilsartan excreted in urine remains unchanged.[1]

Adverse Effects

Overall, azilsartan is well-tolerated in most patients in terms of adverse effects. In a controlled, double-blind, randomized clinical trial comparing the efficacy of azilsartan medoxomil to the ACE inhibitor ramipril in 784 patients, the overall number of adverse events were reported to be much less frequent with azilsartan. Patients were started on a dose of 20 mg of azilsartan and 2.5 mg of ramipril once daily for two weeks, then were titrated up to dosages of 40 or 80 mg of azilsartan and 10 mg of ramipril for 22 weeks.[7]

During the treatment period, dizziness and hypotension occurred more often with the azilsartan treatment groups, and cough, a class side effect commonly encountered with ACE inhibitors, occurred more frequently with the ramipril group (8.2% of participants).[7] Cough only occurred in 1% and 1.4% of azilsartan 40 and 80 mg groups, respectively.[7] Another effect observed in the azilsartan group was a pertinent increase in serum potassium, sodium, and uric acid; no deaths resulted from this effect or the aforementioned adverse effects as well.[7] Adverse events resulting in discontinuation of azilsartan in the treatment groups of 40 and 80 mg were less frequent (2.4% and 3.1%, respectively) than with ramipril (4.8%).[7] There were no recorded events of hyperkalemia or angioedema in this study.

Hypotension/orthostatic hypotension remained the most common adverse effect leading to discontinuation of azilsartan in placebo-controlled trials.[1] Other observed adverse effects, although rare, included diarrhea (less than or equal to 2% in 80 mg treatment groups), nausea, asthenia, and fatigue.[1] Rarer side effects observed are muscle spasms, dizziness, and cough.[1] In less than or equal to 0.4% of patients, low hemoglobin, hematocrit, and decreased number of red blood cells were also noted in patients taking azilsartan.[1]

Contraindications

As previously mentioned, azilsartan is an ARB, in the same drug class as some older antihypertensives such as losartan and valsartan. For all ARBs and other drugs that interfere with the RAAS system such as ACE-inhibitors and direct renin inhibitors, pregnancy is considered an absolute contraindication. Azilsartan is a teratogenic antihypertensive drug; if taken during early pregnancy, the threat of congenital abnormalities rises greatly.[8] ARB drugs are also considered fetotoxic during the second and third trimesters.[2] For this reason, the FDA released a US Boxed Warning explaining the fetal risk with the FDA approval of azilsartan. If a woman has previously been on an ARB such as azilsartan and becomes pregnant, the drug should be discontinued immediately (preferably within two days of pregnancy confirmation), and an alternative should be discussed with a physician.[8] The above mentioned conditions also apply to a woman planning to become pregnant. Evidence has also accumulated involving small levels of azilsartan being present in lactating rats’ milk, although it has not yet been studied in human lactating mothers.[4] 

Although there are no current clinical contraindications to azilsartan medoxomil therapy, it is not advisable to prescribe azilsartan with aliskiren-containing products (direct renin inhibitors) or other medications that impact the RAAS system, such as ACE inhibitors.[2] Randomized controlled trial data suggests that ARB therapy combined with ACE inhibitors or aliskiren increases the risk of cardiovascular and renal problems; this is especially pertinent in those with diabetes mellitus.[2]

If a patient has a history of angioedema with prior ARB use, azilsartan should not be used, as with other ARBs.[2] However, a patient with a history of angioedema as a result of ACE inhibitors can begin treatment with an ARB six weeks after discontinuation of the ACE inhibitor.[2] If azilsartan is combined with chlorthalidone, anuria is a contraindication, along with pregnancy.[6]

Monitoring

In patients with chronic kidney disease or those on potassium supplements or potassium-sparing drugs, the risk for hyperkalemia increases and requires monitoring.[2] In patients diagnosed with severe bilateral renal artery stenosis, acute kidney injury is a risk.[2]

Due to the primary method of metabolism for azilsartan being CYP2C9, once therapy has started, interactions with strong modulators of CYP2C9 should be monitored closely.[1] Combination therapy with other antihypertensive agents should also be monitored, as well as concomitant non-steroidal anti-inflammatory (NSAID) or selective cyclooxygenase (COX-2) inhibitor therapy.[1] Renal function may become impaired with coadministration of NSAIDs or other selective COX-2 inhibitors with azilsartan.[1] This impairment mostly occurs in patients with renal compromise, or those who may be elderly or volume-depleted; for this reason, if NSAIDs are given with azilsartan, the renal function requires periodic monitoring.[1]

Toxicity

No maximum toxic doses have been established yet for azilsartan. Patients on azilsartan with volume depletion, severe heart failure, or renal stenosis are at risk for oliguria or progressive azotemia.[1] Volume or salt depletion should be corrected first before initiating azilsartan.[1]

Enhancing Healthcare Team Outcomes

Although azilsartan is normally well-tolerated, it is always imperative to make sure the interprofessional team is aware of the danger of prescribing ACE inhibitors, aliskiren-containing products, and ARBs together. Physicians, physician assistants, and nurse practitioners must be vigilant in making sure that these drugs are not prescribed together if more than one member of the team is responsible for the patient. Nurses must make sure that the patient accounts for each doctor and medication prescribed to him or her, and pharmacists must make sure that no drug interactions or duplicate therapies occur. It is of the utmost importance for each member of the medical team to verify that a female patient of child-bearing age is not pregnant before prescribing azilsartan or any other ARB.


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.

Azilsartan - Questions

Take a quiz of the questions on this article.

Take Quiz
A patient has been prescribed captopril to treat his hypertension. He has complained of a dry cough that has been persistent ever since he started his therapy. What medication is the next alternative for this patient that also acts on the renin-angiotensin-aldosterone system and will have a less likelihood of a cough?



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
What is the drug class of Edarbi?



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 patient presents to an ambulatory clinic with consistent blood pressure readings of 152/95 mmHg from the past few months. She shows signs and symptoms of bilateral edema in her legs and was diagnosed with diabetes mellitus three years ago. Upon reviewing her chart, it shows that she has experienced albuminuria recently. Which medication would be the most effective in reducing her symptoms and lowering her blood pressure?



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

Azilsartan - References

References

Jones JD,Jackson SH,Agboton C,Martin TS, Azilsartan Medoxomil (Edarbi): The Eighth Angiotensin II Receptor Blocker. P     [PubMed]
Whelton PK,Carey RM,Aronow WS,Casey DE Jr,Collins KJ,Dennison Himmelfarb C,DePalma SM,Gidding S,Jamerson KA,Jones DW,MacLaughlin EJ,Muntner P,Ovbiagele B,Smith SC Jr,Spencer CC,Stafford RS,Taler SJ,Thomas RJ,Williams KA Sr,Williamson JD,Wright JT Jr, 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Journal of the American College of Cardiology. 2018 May 15;     [PubMed]
Hjermitslev M,Grimm DG,Wehland M,Simonsen U,Krüger M, Azilsartan Medoxomil, an Angiotensin II Receptor Antagonist for the Treatment of Hypertension. Basic     [PubMed]
De Caterina AR,Harper AR,Cuculi F, Critical evaluation of the efficacy and tolerability of azilsartan. Vascular health and risk management. 2012;     [PubMed]
Sparks MA,Crowley SD,Gurley SB,Mirotsou M,Coffman TM, Classical Renin-Angiotensin system in kidney physiology. Comprehensive Physiology. 2014 Jul;     [PubMed]
Angeloni E, Azilsartan medoxomil in the management of hypertension: an evidence-based review of its place in therapy. Core evidence. 2016;     [PubMed]
Bönner G,Bakris GL,Sica D,Weber MA,White WB,Perez A,Cao C,Handley A,Kupfer S, Antihypertensive efficacy of the angiotensin receptor blocker azilsartan medoxomil compared with the angiotensin-converting enzyme inhibitor ramipril. Journal of human hypertension. 2013 Aug;     [PubMed]
Lu Y,Chen R,Cai J,Huang Z,Yuan H, The management of hypertension in women planning for pregnancy. British medical bulletin. 2018 Dec 1;     [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 Optometry-Basic Science. 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 Optometry-Basic Science, 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 Optometry-Basic Science, 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 Optometry-Basic Science. When it is time for the Optometry-Basic Science 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 Optometry-Basic Science.