Chemistry:Candesartan

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Candesartan is an angiotensin receptor blocker (ARB) primarily used to treat high blood pressure and congestive heart failure. It is always administered in its inactive prodrug form, candesartan cilexetil, which is converted to the active drug during absorption in the gastrointestinal tract. Like olmesartan, candesartan is a cascading prodrug, a feature that influences its pharmacokinetics. It has good bioavailability and is considered one of the most potent AT1 receptor antagonists by weight. Its effective maintenance dose is also relatively low.

It was patented in 1990 and approved for medical use in 1997.[1]

Medical uses

Hypertension

As with other angiotensin II receptor antagonists, candesartan is indicated for the treatment of hypertension.[2] 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.[citation needed]

Heart failure

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.[3][4] 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%).[4][5]

Prehypertension

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.[6]

Prevention of atrial fibrillation

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.[7] 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.[8] 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.[citation needed]

Diabetic retinopathy

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.[9][10][11] 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.[10] Candesartan has been demonstrated to reverse the severity (cause regression) of mild to moderate diabetic retinopathy in patients with type 2 diabetes.[11] 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.[10][11]

Migraine prophylaxis

Candesartan may be helpful in migraine prevention as it has better tolerability and fewer side effects compared to other first line medications.[12][13] It has been recommended by multiple guidelines for migraine prophylaxis in adults with different levels of recommendations,[14][15][16][17][18] however further studies on larger populations are needed.

Depression and bipolar depression

Candesartan is currently being investigated as a potential adjunct therapy for both depression and bipolar depression in the CADET (Candesartan Adjunctive Trials) clinical trials.[19] These studies—one for major depressive disorder and one for bipolar depression—are double-blind, placebo-controlled clinical trials.[19] The proposed mechanism of action is via antagonism of the AT-1 receptor, which a 2017 meta-analysis indicated may have effects on mental health.[20] As Candesartan is a strong AT-1 receptor antagonist, it was selected for the clinical trial.

Adverse effects

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.[2]

Anemia may occur, due to inhibition of the renin–angiotensin system.[21]

As with other angiotensin receptor blockers, candesartan can rarely cause severe liver injury.[22]

Pharmacokinetics

Candesartan cilexetil metabolic activation

Candesartan is administered clinically as the cyclohexyl 1-hydroxy ethyl carbonate ester, known as candesartan cilexetil. It is a cascading prodrug that is completely metabolised by esterases in the intestinal wall during absorption, releasing the active candesartan moiety. In the first step of the activation process, the carbonate group is hydrolyzed, releasing carbon dioxide. This reaction also produces cyclohexanol, a relatively non-toxic byproduct that contributes to the favorable safety profile of the prodrug. Another side product of the cascading mechanism is acetic acid, derived from the hydrolysis of the O-CH(CH3)- group; like cyclohexanol, it is also non-toxic and poses minimal risk during drug activation.[citation needed]

The use of the prodrug form, candesartan cilexetil, enhances the bioavailability of candesartan. However, its absolute bioavailability remains relatively low, ranging from approximately 15% when administered as tablets to 40% as an oral solution. Candesartan has an IC50 of 15 μg/kg. The active form of candesartan is not used directly in clinical practice, as it would require higher dosing and is associated with a less favorable adverse event profile.[citation needed]

Research

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[23] and it is being examined as a potential treatment for early Alzheimer's.[24] Rat models indicate that candesartan may have neuroprotective benefits that mitigate certain central mechanisms of ageing and senescence.[25] Additionally, candesartan has shown potential therapeutic applications as an anti-anxiety agent.[26] 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.[27] The unique anti-oxidative and anti-inflammatory effects of Candesartan are shown to offer superior renoprotection of chronic renal inflammation,[28] and in ultrahigh doses and in a multidrug context, could be investigated as potentially inducing remission of chronic kidney disease.[29]

History

See also: Chemistry: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.[30][31]

Names

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.[citation needed]

References

  1. ↑ (in en) Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 471. ISBN 978-3-527-60749-5. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA471. 
  2. ↑ 2.0 2.1 "Candesartan label". FDA. February 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020838s039lbl.pdf.  For label updates see FDA index page for IND 020838
  3. ↑ "A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure". The New England Journal of Medicine 345 (23): 1667–1675. December 2001. doi:10.1056/NEJMoa010713. PMID 11759645. 
  4. ↑ 4.0 4.1 "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". Lancet 362 (9386): 772–776. September 2003. doi:10.1016/S0140-6736(03)14284-5. PMID 13678870. 
  5. ↑ "Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme". Lancet 362 (9386): 759–766. September 2003. doi:10.1016/s0140-6736(03)14282-1. PMID 13678868. 
  6. ↑ "Feasibility of treating prehypertension with an angiotensin-receptor blocker". The New England Journal of Medicine 354 (16): 1685–1697. April 2006. doi:10.1056/NEJMoa060838. PMID 16537662. 
  7. ↑ "Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: a meta-analysis". Journal of the American College of Cardiology 45 (11): 1832–1839. June 2005. doi:10.1016/j.jacc.2004.11.070. PMID 15936615. 
  8. ↑ "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". American Heart Journal 151 (5): 985–991. May 2006. doi:10.1016/j.ahj.2005.06.036. PMID 16644318. 
  9. ↑ "Evidence and indications for systemic treatment in diabetic retinopathy: a systematic review". Acta Ophthalmologica 98 (4): 329–336. June 2020. doi:10.1111/aos.14377. PMID 32100477. 
  10. ↑ 10.0 10.1 10.2 "Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials". Lancet 372 (9647): 1394–1402. October 2008. doi:10.1016/S0140-6736(08)61412-9. PMID 18823656. 
  11. ↑ 11.0 11.1 11.2 "Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial". Lancet 372 (9647): 1385–1393. October 2008. doi:10.1016/S0140-6736(08)61411-7. PMID 18823658. 
  12. ↑ "A comparative study of candesartan versus propranolol for migraine prophylaxis: A randomised, triple-blind, placebo-controlled, double cross-over study". Cephalalgia 34 (7): 523–532. June 2014. doi:10.1177/0333102413515348. PMID 24335848. 
  13. ↑ "Real world effectiveness and tolerability of candesartan in the treatment of migraine: a retrospective cohort study". Scientific Reports 11 (1). February 2021. doi:10.1038/s41598-021-83508-2. PMID 33589682. Bibcode: 2021NatSR..11.3846S. 
  14. ↑ "Therapeutic Guidelines | Therapeutic Guidelines". https://tgldcdp.tg.org.au/etgcomplete. 
  15. ↑ "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". Neurology 78 (17): 1337–1345. April 2012. doi:10.1212/wnl.0b013e3182535d20. PMID 22529202. 
  16. ↑ "Pharmacologic prevention of migraine". CMAJ 195 (5): E187–E192. February 2023. doi:10.1503/cmaj.221607. PMID 36746481. 
  17. ↑ "Guidelines" (in en-US). https://headachesociety.ca/guidelines/. 
  18. ↑ "EFNS guideline on the drug treatment of migraine--revised report of an EFNS task force". European Journal of Neurology 16 (9): 968–981. September 2009. doi:10.1111/j.1468-1331.2009.02748.x. PMID 19708964. 
  19. ↑ 19.0 19.1 "Repurposing Candesartan, the Antihypertensive Drug, for Treatment of Bipolar Disorder". International Journal of Neuropsychopharmacology 28 (Supplement_1): i121–i122. 2025-02-01. doi:10.1093/ijnp/pyae059.209. ISSN 1469-5111. PMC 11814688. https://academic.oup.com/ijnp/article/28/Supplement_1/i121/8009724. 
  20. ↑ "Blockade of the angiotensin system improves mental health domain of quality of life: A meta-analysis of randomized clinical trials" (in en). Australian & New Zealand Journal of Psychiatry 52 (1): 24–38. 2018-01-01. doi:10.1177/0004867417721654. ISSN 0004-8674. PMID 28754072. https://journals.sagepub.com/doi/10.1177/0004867417721654. 
  21. ↑ "Renin-angiotensin system inhibitors linked to anemia: a systematic review and meta-analysis". QJM 108 (11): 879–884. November 2015. doi:10.1093/qjmed/hcv049. PMID 25697787.  open access
  22. ↑ "Losartan-induced Severe Hepatic Injury: A Case Report and Literature Review". Cureus 11 (5). May 2019. doi:10.7759/cureus.4769. PMID 31363450. 
  23. ↑ "Candesartan ameliorates brain inflammation associated with Alzheimer's disease". CNS Neuroscience & Therapeutics 24 (3): 231–242. March 2018. doi:10.1111/cns.12802. PMID 29365370. 
  24. ↑ "Evidence to Consider Angiotensin II Receptor Blockers for the Treatment of Early Alzheimer's Disease". Cellular and Molecular Neurobiology 36 (2): 259–279. March 2016. doi:10.1007/s10571-015-0327-y. PMID 26993513. 
  25. ↑ "Candesartan Neuroprotection in Rat Primary Neurons Negatively Correlates with Aging and Senescence: a Transcriptomic Analysis". Molecular Neurobiology 57 (3): 1656–1673. March 2020. doi:10.1007/s12035-019-01800-9. PMID 31811565. 
  26. ↑ "A centrally acting, anxiolytic angiotensin II AT1 receptor antagonist prevents the isolation stress-induced decrease in cortical CRF1 receptor and benzodiazepine binding". Neuropsychopharmacology 31 (6): 1123–1134. June 2006. doi:10.1038/sj.npp.1300921. PMID 16205776. 
  27. ↑ "The effects of candesartan on left ventricular hypertrophy and function in nonobstructive hypertrophic cardiomyopathy: a pilot, randomized study". The Journal of Molecular Diagnostics 11 (1): 35–41. January 2009. doi:10.2353/jmoldx.2009.080082. PMID 19074594. 
  28. ↑ "Candesartan suppresses chronic renal inflammation by a novel antioxidant action independent of AT1R blockade". Kidney International 74 (9): 1128–1138. Nov 2008. doi:10.1038/ki.2008.380. PMID 18650791. 
  29. ↑ "Candesartan and renal protection: more than blocking angiotensin type 1 receptor?". Kidney International 74 (9): 1112–1114. 2008. doi:10.1038/ki.2008.420. PMID 18854846. 
  30. ↑ "Hypotensive activity of TCV-116, a newly developed angiotensin II receptor antagonist, in spontaneously hypertensive rats". Life Sciences 51 (20): PL183–PL187. 1992. doi:10.1016/0024-3205(92)90627-2. PMID 1435062. 
  31. ↑ "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". Clinical Therapeutics 15 (4): 684–691. Jul–Aug 1993. PMID 8221818. 



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