Candesartan

As with other angiotensin II receptor antagonists, candesartan is indicated for the treatment of hypertension. Candesartan has an additive antihypertensive effect when combined with a diuretic, such as chlorthalidone. It is available in a fixed-combination formulation with a low dose of the thiazide diuretic hydrochlorothiazide. Candesartan/hydrochlorothiazide combination preparations are marketed under various trade names including Atacand Plus, Hytacand, Blopress Plus, Advantec and Ratacand Plus.{{cn|date=February 2025}}

In heart failure patients, angiotensin receptor blockers such as candesartan and valsartan may be a suitable option for those who do not tolerate angiotensin-converting enzyme inhibitor medicines.{{cite journal | vauthors = Cohn JN, Tognoni G | title = A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure | journal = The New England Journal of Medicine | volume = 345 | issue = 23 | pages = 1667–1675 | date = December 2001 | pmid = 11759645 | doi = 10.1056/NEJMoa010713 | doi-access = free }}{{cite journal | vauthors = Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, Ostergren J, Pfeffer MA, Swedberg K | display-authors = 6 | collaboration = CHARM Investigators and Committees | title = Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial | journal = Lancet | volume = 362 | issue = 9386 | pages = 772–776 | date = September 2003 | doi = 10.1016/S0140-6736(03)14284-5 | pmid = 13678870 | s2cid = 5650345 }} Randomised control trials have shown candesartan reduces heart failure hospitalisations and cardiovascular deaths for patients who have heart failure with reduced left ventricular ejection fraction (LVEF ≤ 40%).{{cite journal | vauthors = Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J, Yusuf S, Pocock S | display-authors = 6 | title = Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme | journal = Lancet | volume = 362 | issue = 9386 | pages = 759–766 | date = September 2003 | pmid = 13678868 | doi = 10.1016/s0140-6736(03)14282-1 | s2cid = 15011437 }}

In a four-year randomized controlled trial, candesartan was compared to placebo to see whether it could prevent or postpone the development of full-blown hypertension in people with so-called prehypertension. During the first two years of the trial, half of participants were given candesartan while the other half received placebo; candesartan reduced the risk of developing hypertension by nearly two-thirds during this period. In the last two years of the study, all participants were switched to placebo. By the end of the study, candesartan had significantly reduced the risk of hypertension, by more than 15%. Serious adverse effects were more common among participants receiving placebo than in those given candesartan.{{cite journal | vauthors = Julius S, Nesbitt SD, Egan BM, Weber MA, Michelson EL, Kaciroti N, Black HR, Grimm RH, Messerli FH, Oparil S, Schork MA | display-authors = 6 | title = Feasibility of treating prehypertension with an angiotensin-receptor blocker | journal = The New England Journal of Medicine | volume = 354 | issue = 16 | pages = 1685–1697 | date = April 2006 | pmid = 16537662 | doi = 10.1056/NEJMoa060838 | doi-access = free }}

In 2005, meta-analysis results showed that angiotensin receptor blockers and angiotensin converting enzyme inhibitors considerably reduce the risk of atrial fibrillation in patients with coexisting heart failure and systolic left ventricular dysfunction.{{cite journal | vauthors = Healey JS, Baranchuk A, Crystal E, Morillo CA, Garfinkle M, Yusuf S, Connolly SJ | title = Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: a meta-analysis | journal = Journal of the American College of Cardiology | volume = 45 | issue = 11 | pages = 1832–1839 | date = June 2005 | pmid = 15936615 | doi = 10.1016/j.jacc.2004.11.070 | doi-access = free }} Specifically, an analysis of the CHARM study showed benefits for Candesartan in reducing new occurrences of atrial fibrillation in patients with heart failure and reduced left ventricular function.{{cite journal | vauthors = Ducharme A, Swedberg K, Pfeffer MA, Cohen-Solal A, Granger CB, Maggioni AP, Michelson EL, McMurray JJ, Olsson L, Rouleau JL, Young JB, Yusuf S | display-authors = 6 | title = Prevention of atrial fibrillation in patients with symptomatic chronic heart failure by candesartan in the Candesartan in Heart failure: assessment of Reduction in Mortality and morbidity (CHARM) program | journal = American Heart Journal | volume = 151 | issue = 5 | pages = 985–991 | date = May 2006 | pmid = 16644318 | doi = 10.1016/j.ahj.2005.06.036 }} While these studies have demonstrated a potential additional benefit for candesartan when used in patients with systolic left ventricular dysfunction, additional studies are required to further elucidate the role of candesartan in the prevention of atrial fibrillation in other population groups.{{cn|date=February 2025}}

Use of antihypertensive drugs has been demonstrated to slow the progression of diabetic retinopathy; the role of candesartan specifically in reducing progression in type 1 and type 2 diabetes is still up for debate.{{cite journal | vauthors = Elkjaer AS, Lynge SK, Grauslund J | title = Evidence and indications for systemic treatment in diabetic retinopathy: a systematic review | journal = Acta Ophthalmologica | volume = 98 | issue = 4 | pages = 329–336 | date = June 2020 | pmid = 32100477 | doi = 10.1111/aos.14377 | s2cid = 211523341 | doi-access = free }}{{cite journal | vauthors = Chaturvedi N, Porta M, Klein R, Orchard T, Fuller J, Parving HH, Bilous R, Sjølie AK | display-authors = 6 | title = Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials | journal = Lancet | volume = 372 | issue = 9647 | pages = 1394–1402 | date = October 2008 | pmid = 18823656 | doi = 10.1016/S0140-6736(08)61412-9 | s2cid = 20796943 }}{{cite journal | vauthors = Sjølie AK, Klein R, Porta M, Orchard T, Fuller J, Parving HH, Bilous R, Chaturvedi N | display-authors = 6 | title = Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial | journal = Lancet | volume = 372 | issue = 9647 | pages = 1385–1393 | date = October 2008 | pmid = 18823658 | doi = 10.1016/S0140-6736(08)61411-7 | s2cid = 15210734 }} Results from a 2008 study on patients with type 1 diabetes showed there was no benefit in using candesartan to reduce progression of diabetic retinopathy when compared to placebo. Candesartan has been demonstrated to reverse the severity (cause regression) of mild to moderate diabetic retinopathy in patients with type 2 diabetes. The patient populations investigated in these studies were limited to mostly Caucasians and those younger than 75 years of age, so generalization of these findings to other population groups should be done with caution.

Candesartan may be helpful in migraine prevention as it has better tolerability and fewer side effects compared to other first line medications.{{cite journal | vauthors = Stovner LJ, Linde M, Gravdahl GB, Tronvik E, Aamodt AH, Sand T, Hagen K | title = A comparative study of candesartan versus propranolol for migraine prophylaxis: A randomised, triple-blind, placebo-controlled, double cross-over study | journal = Cephalalgia | volume = 34 | issue = 7 | pages = 523–532 | date = June 2014 | pmid = 24335848 | doi = 10.1177/0333102413515348 | s2cid = 24678271 }}{{cite journal | vauthors = Sánchez-Rodríguez C, Sierra Á, Planchuelo-Gómez Á, Martínez-Pías E, Guerrero ÁL, García-Azorín D | title = Real world effectiveness and tolerability of candesartan in the treatment of migraine: a retrospective cohort study | journal = Scientific Reports | volume = 11 | issue = 1 | pages = 3846 | date = February 2021 | pmid = 33589682 | pmc = 7884682 | doi = 10.1038/s41598-021-83508-2 | bibcode = 2021NatSR..11.3846S }} It has been recommended by multiple guidelines for migraine prophylaxis in adults with different levels of recommendations,{{Cite web |title=Therapeutic Guidelines {{!}} Therapeutic Guidelines |url=https://tgldcdp.tg.org.au/etgcomplete |access-date=2023-05-12 |website=tgldcdp.tg.org.au}}{{cite journal | vauthors = Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E | title = Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society | journal = Neurology | volume = 78 | issue = 17 | pages = 1337–1345 | date = April 2012 | pmid = 22529202 | pmc = 3335452 | doi = 10.1212/wnl.0b013e3182535d20 | s2cid = 8597108 }}{{cite journal | vauthors = Tzankova V, Becker WJ, Chan TL | title = Pharmacologic prevention of migraine | journal = CMAJ | volume = 195 | issue = 5 | pages = E187–E192 | date = February 2023 | pmid = 36746481 | pmc = 9904820 | doi = 10.1503/cmaj.221607 | s2cid = 256598489 }}{{Cite web |title=Guidelines |url=https://headachesociety.ca/guidelines/ |access-date=2023-05-12 |website=Canadian Headache Society |language=en-US |archive-date=2023-05-12 |archive-url=https://web.archive.org/web/20230512033420/https://headachesociety.ca/guidelines/ |url-status=dead }}{{cite journal | vauthors = Evers S, Afra J, Frese A, Goadsby PJ, Linde M, May A, Sándor PS | title = EFNS guideline on the drug treatment of migraine--revised report of an EFNS task force | journal = European Journal of Neurology | volume = 16 | issue = 9 | pages = 968–981 | date = September 2009 | pmid = 19708964 | doi = 10.1111/j.1468-1331.2009.02748.x | s2cid = 9204782 | doi-access = free }} however further studies on larger populations are needed.

As with other drugs that inhibit the renin–angiotensin system, if candesartan is taken by pregnant women during the second or third trimester, it can cause injury and in some cases, death of the developing fetus. Symptomatic hypotension may occur in people who take candesartan and are volume-depleted or salt-depleted, as can also occur when diuretics are coadministered. Reduction in renal glomerular filtration rate may occur; people with renal artery stenosis may be at higher risk. Hyperkalemia may occur; people who are also taking spironolactone or eplerenone may be at higher risk.{{cite web|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020838s039lbl.pdf|title=Candesartan label|publisher=FDA|date=February 2016}} For label updates see [https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=020838 FDA index page for IND 020838]

Anemia may occur, due to inhibition of the renin–angiotensin system.{{cite journal | vauthors = Cheungpasitporn W, Thongprayoon C, Chiasakul T, Korpaisarn S, Erickson SB | title = Renin-angiotensin system inhibitors linked to anemia: a systematic review and meta-analysis | journal = QJM | volume = 108 | issue = 11 | pages = 879–884 | date = November 2015 | pmid = 25697787 | doi = 10.1093/qjmed/hcv049 | doi-access = free }} {{open access}}

As with other angiotensin receptor blockers, candesartan can rarely cause severe liver injury.{{cite journal | vauthors = Patti R, Sinha A, Sharma S, Yoon TS, Kupfer Y | title = Losartan-induced Severe Hepatic Injury: A Case Report and Literature Review | journal = Cureus | volume = 11 | issue = 5 | pages = e4769 | date = May 2019 | pmid = 31363450 | pmc = 6663042 | doi = 10.7759/cureus.4769 | doi-access = free }}

Image:Candesartan Cilexetil.svg

Candesartan is marketed as the cyclohexyl 1-hydroxy ethyl carbonate (cilexetil) ester, known as candesartan cilexetil. Candesartan cilexetil is metabolised completely by esterases in the intestinal wall during absorption to the active candesartan moiety. In the first step of the cascading pro-drug mechanism, the carbonate group is hydrolyzed, releasing carbon dioxide. The metabolite at this step is cyclohexanol which, being relatively non-toxic, is advantageous to the design of the drug. The other aspect of the cascading prodrug is the O-CH-CH3 molecule which becomes converted into acetic acid, which is another product from the cascading side reaction. Similar to the insight from cyclohexanol, the metabolite of acetic acid relatively is non-toxic and thus less of a hazard if produced as the drug takes pharmacologic action.{{cn|date=February 2025}}

The use of a prodrug form increases the bioavailability of candesartan. Despite this, absolute bioavailability is relatively poor at 15% (candesartan cilexetil tablets) to 40% (candesartan cilexetil solution). Its IC₅₀ is 15 μg/kg. Candesartan is not administered in its active form because the administration of the pro-drug would require greater doses and has an unfavorable adverse event profile.{{cn|date=February 2025}}

There is ongoing research into several potential benefits of candesartan beyond established indications. Candesartan is being investigated for its neuroprotective and anti-inflammatory properties. In an early Alzheimer's disease mouse model, candesartan significantly reduced amyloid burden and inflammation{{cite journal | vauthors = Torika N, Asraf K, Apte RN, Fleisher-Berkovich S | title = Candesartan ameliorates brain inflammation associated with Alzheimer's disease | journal = CNS Neuroscience & Therapeutics | volume = 24 | issue = 3 | pages = 231–242 | date = March 2018 | pmid = 29365370 | pmc = 6489976 | doi = 10.1111/cns.12802 }} and it is being examined as a potential treatment for early Alzheimer's.{{cite journal | vauthors = Saavedra JM | title = Evidence to Consider Angiotensin II Receptor Blockers for the Treatment of Early Alzheimer's Disease | journal = Cellular and Molecular Neurobiology | volume = 36 | issue = 2 | pages = 259–279 | date = March 2016 | pmid = 26993513 | doi = 10.1007/s10571-015-0327-y | pmc = 11482317 | s2cid = 254384149 }} Rat models indicate that candesartan may have neuroprotective benefits that mitigate certain central mechanisms of ageing and senescence.{{cite journal | vauthors = Elkahloun AG, Saavedra JM | title = Candesartan Neuroprotection in Rat Primary Neurons Negatively Correlates with Aging and Senescence: a Transcriptomic Analysis | journal = Molecular Neurobiology | volume = 57 | issue = 3 | pages = 1656–1673 | date = March 2020 | pmid = 31811565 | pmc = 7062590 | doi = 10.1007/s12035-019-01800-9 }} Additionally, candesartan has shown potential therapeutic applications as an anti-anxiety agent.{{cite journal | vauthors = Saavedra JM, Armando I, Bregonzio C, Juorio A, Macova M, Pavel J, Sanchez-Lemus E | title = A centrally acting, anxiolytic angiotensin II AT1 receptor antagonist prevents the isolation stress-induced decrease in cortical CRF1 receptor and benzodiazepine binding | journal = Neuropsychopharmacology | volume = 31 | issue = 6 | pages = 1123–1134 | date = June 2006 | pmid = 16205776 | doi = 10.1038/sj.npp.1300921 | s2cid = 23912388 | doi-access = free }} In a double-blind, placebo-controlled, randomized study, candesartan induced regression of left ventricular hypertrophy, and improved both LV function and exercise tolerance with no side effects in patients with non-obstructive hypertrophic cardiomyopathy.{{cite journal | vauthors = Penicka M, Gregor P, Kerekes R, Marek D, Curila K, Krupicka J | title = The effects of candesartan on left ventricular hypertrophy and function in nonobstructive hypertrophic cardiomyopathy: a pilot, randomized study | journal = The Journal of Molecular Diagnostics | volume = 11 | issue = 1 | pages = 35–41 | date = January 2009 | pmid = 19074594 | pmc = 2607563 | doi = 10.2353/jmoldx.2009.080082 }} The unique anti-oxidative and anti-inflammatory effects of Candesartan are shown to offer superior renoprotection of chronic renal inflammation,{{cite journal | vauthors = Chen S, Ge Y, Si J, Rifai A, Dworkin LD, Gong R | title = Candesartan suppresses chronic renal inflammation by a novel antioxidant action independent of AT1R blockade | journal = Kidney International | volume = 74 | issue = 9 | pages = 1128–1138 | date = Nov 2008 | pmid = 18650791 | doi = 10.1038/ki.2008.380 | doi-access = free }} and in ultrahigh doses and in a multidrug context, could be investigated as potentially inducing remission of chronic kidney disease.{{cite journal | vauthors = Macconi D, Remuzzi G | title = Candesartan and renal protection: more than blocking angiotensin type 1 receptor? | journal = Kidney International | volume = 74 | issue = 9 | pages = 1112–1114 | date = 2008 | doi = 10.1038/ki.2008.420 | doi-access = free | pmid = 18854846 }}

{{See also|Discovery and development of angiotensin receptor blockers}}

The compound known as TCV-116 (candesartan) was studied by Japanese scientists using standard laboratory rats. Animal studies were published showing the effectiveness of the compound in 1992–1993, with a pilot study on humans published in the summer of 1993.{{cite journal | vauthors = Mizuno K, Niimura S, Tani M, Saito I, Sanada H, Takahashi M, Okazaki K, Yamaguchi M, Fukuchi S | display-authors = 6 | title = Hypotensive activity of TCV-116, a newly developed angiotensin II receptor antagonist, in spontaneously hypertensive rats | journal = Life Sciences | volume = 51 | issue = 20 | pages = PL183–PL187 | date = 1992 | pmid = 1435062 | doi = 10.1016/0024-3205(92)90627-2 }}{{cite journal | vauthors = Ogihara T, Higashimori K, Masuo K, Mikami H | title = Pilot study of a new angiotensin II receptor antagonist, TCV-116: effects of a single oral dose on blood pressure in patients with essential hypertension | journal = Clinical Therapeutics | volume = 15 | issue = 4 | pages = 684–691 | date = Jul–Aug 1993 | pmid = 8221818 }}

The prodrug candesartan cilexetil is marketed by AstraZeneca and Takeda Pharmaceuticals, commonly under the trade names Blopress, Atacand, Amias, and Ratacand. It is available in generic form.{{cn|date=February 2025}}

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