Candesartan

Last updated
Candesartan
Candesartan.svg
Clinical data
Pronunciation /ˌkændɪˈsɑːrtən/
Trade names Atacand, others
Other namesCandesartan cilexetil
AHFS/Drugs.com Monograph
MedlinePlus a601033
Pregnancy
category
  • AU:D
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
  • US: WARNING [1]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 15% (candesartan cilexetil)
Metabolism Candesartan cilexetil: intestinal wall; candesartan: hepatic (CYP2C9)
Elimination half-life 9 hours
Excretion Kidney 33%, faecal 67%
Identifiers
  • 2-ethoxy-1-({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1H-1,3-benzodiazole-7-carboxylic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.132.654 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C24H20N6O3
Molar mass 440.463 g·mol−1
3D model (JSmol)
  • CCOc2nc1cccc(C(=O)O)c1n2Cc5ccc(c3ccccc3c4nn[nH]n4)cc5
  • InChI=1S/C24H20N6O3/c1-2-33-24-25-20-9-5-8-19(23(31)32)21(20)30(24)14-15-10-12-16(13-11-15)17-6-3-4-7-18(17)22-26-28-29-27-22/h3-13H,2,14H2,1H3,(H,31,32)(H,26,27,28,29) Yes check.svgY
  • Key:HTQMVQVXFRQIKW-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Candesartan is an angiotensin receptor blocker used mainly for the treatment of high blood pressure and congestive heart failure. Candesartan has a very low maintenance dose. Like olmesartan, the metabolism of the drug is unusual as it is a cascading prodrug. Candesartan has good bioavailibility and is the most potent by weight of the AT-1 receptor antagonists.

Contents

It was patented in 1990 and approved for medical use in 1997. [2]

Medical uses

Hypertension

As with other angiotensin II receptor antagonists, candesartan is indicated for the treatment of hypertension. [3] 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.

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. [4] [5] 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%). [5] [6]

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. [7]

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. [8] 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. [9] 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.

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. [10] [11] [12] 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. [11] Candesartan has been demonstrated to reverse the severity (cause regression) of mild to moderate diabetic retinopathy in patients with type 2 diabetes. [12] 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. [11] [12]

Migraine prophylaxis

Candesartan may be helpful in migraine prevention as it has better tolerability and less side effects compared to other first line medications. [13] [14] It has been recommended by multiple guidelines for migraine prophylaxis in adults with different levels of recommendations, [15] [16] [17] [18] [19] however further studies on larger populations are needed.

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. [3]

Anemia may occur, due to inhibition of the renin–angiotensin system. [20]

As with other angiotensin receptor blockers, candesartan can rarely cause severe liver injury. [21]

Candesartan cilexetil Candesartan Cilexetil.svg
Candesartan cilexetil

Chemistry and pharmacokinetics

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.

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.

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

History

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. [29] [30]

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.

Related Research Articles

<span class="mw-page-title-main">ACE inhibitor</span> Class of medications used primarily to treat high blood pressure

Angiotensin-converting-enzyme inhibitors are a class of medication used primarily for the treatment of high blood pressure and heart failure. This class of medicine works by causing relaxation of blood vessels as well as a decrease in blood volume, which leads to lower blood pressure and decreased oxygen demand from the heart.

<span class="mw-page-title-main">Beta blocker</span> Medications for abnormal heart rhythms

Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms (arrhythmia), and to protect the heart from a second heart attack after a first heart attack. They are also widely used to treat high blood pressure, although they are no longer the first choice for initial treatment of most patients.

Antihypertensives are a class of drugs that are used to treat hypertension. Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke, heart failure, kidney failure and myocardial infarction. Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34% and of ischaemic heart disease by 21%, and can reduce the likelihood of dementia, heart failure, and mortality from cardiovascular disease. There are many classes of antihypertensives, which lower blood pressure by different means. Among the most important and most widely used medications are thiazide diuretics, calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists (ARBs), and beta blockers.

<span class="mw-page-title-main">Diltiazem</span> Calcium channel blocker medication

Diltiazem, sold under the brand name Cardizem among others, is a nondihydropyridine calcium channel blocker medication used to treat high blood pressure, angina, and certain heart arrhythmias. It may also be used in hyperthyroidism if beta blockers cannot be used. It is taken by mouth or injection into a vein. When given by injection, effects typically begin within a few minutes and last a few hours.

<span class="mw-page-title-main">Fosinopril</span> Antihypertensive drug of the ACE inhibitor class

Fosinopril is an angiotensin converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of chronic heart failure. Fosinopril is the only phosphonate-containing ACE inhibitor marketed, by Bristol-Myers Squibb under the trade name Monopril. Fosinopril is a cascading pro-drug. The special niche for the medication that differentiates it from the other members of the ACE Inhibitor drug class is that was specifically developed for the use for patients with renal impairment. This was through manipulation of the metabolism and excretion, and is seen that fifty percent of the drug is hepatobiliary cleared, which can compensate for diminished renal clearance. The remaining fifty percent is excreted in urine. It does not need dose adjustment.

<span class="mw-page-title-main">Angiotensin II receptor blocker</span> Group of pharmaceuticals that modulate the renin–angiotensin system

Angiotensin II receptor blockers (ARBs), formally angiotensin II receptor type 1 (AT1) antagonists, also known as angiotensin receptor blockers, angiotensin II receptor antagonists, or AT1 receptor antagonists, are a group of pharmaceuticals that bind to and inhibit the angiotensin II receptor type 1 (AT1) and thereby block the arteriolar contraction and sodium retention effects of renin–angiotensin system.

<span class="mw-page-title-main">Nadolol</span> Non-selective beta blocker used in the treatment of high blood pressure and chest pain

Nadolol, sold under the brand name Corgard among others, is a medication used to treat high blood pressure, heart pain, atrial fibrillation, and some inherited arrhythmic syndromes. It has also been used to prevent migraine headaches and complications of cirrhosis. It is taken orally.

<span class="mw-page-title-main">Ramipril</span> ACE inhibitor medication

Ramipril, sold under the brand name Altace among others, is an ACE inhibitor type medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It can also be used as a preventative medication in patients over 55 years old to reduce the risk of having a heart attack, stroke or cardiovascular death in patients shown to be at high risk, such as some diabetics and patients with vascular disease. It is a reasonable initial treatment for high blood pressure. It is taken by mouth.

<span class="mw-page-title-main">Valsartan</span> Angiotensin II receptor antagonist

Valsartan, sold under the brand name Diovan among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It belongs to a class of medications referred to as angiotensin II receptor blockers (ARBs). It is a reasonable initial treatment for high blood pressure. It is taken by mouth.

<span class="mw-page-title-main">Hypertensive heart disease</span> Medical condition

Hypertensive heart disease includes a number of complications of high blood pressure that affect the heart. While there are several definitions of hypertensive heart disease in the medical literature, the term is most widely used in the context of the International Classification of Diseases (ICD) coding categories. The definition includes heart failure and other cardiac complications of hypertension when a causal relationship between the heart disease and hypertension is stated or implied on the death certificate. In 2013 hypertensive heart disease resulted in 1.07 million deaths as compared with 630,000 deaths in 1990.

<span class="mw-page-title-main">Perindopril</span> High blood pressure medication

Perindopril is a medication used to treat high blood pressure, heart failure, or stable coronary artery disease.

<span class="mw-page-title-main">Dronedarone</span> Medication

Dronedarone, sold under the brand name Multaq, is a class III antiarrhythmic medication developed by Sanofi-Aventis. It was approved by the US Food and Drug Administration (FDA) in July 2009. Besides being indicated in arrhythmias, it was recommended as an alternative to amiodarone for the treatment of atrial fibrillation and atrial flutter in people whose hearts have either returned to normal rhythm or who undergo drug therapy or electric shock treatment i.e. direct current cardioversion (DCCV) to maintain normal rhythm. It is a class III antiarrhythmic drug. The FDA label includes a claim for reducing hospitalization, but not for reducing mortality, as a reduction in mortality was not demonstrated in the clinical development program. A trial of the drug in heart failure was stopped as an interim analysis showed a possible increase in heart failure deaths, in people with moderate to severe congestive heart failure.

<span class="mw-page-title-main">Landiolol</span> Chemical compound

Landiolol (INN) is an ultra short-acting, β1-superselective intravenous adrenergic antagonist, which decreases the heart rate effectively with less negative effect on blood pressure or myocardial contractility. In comparison to other beta blockers, landiolol has the shortest elimination half-life, ultra-rapid onset of effect, and predictable effectiveness with inactive metabolites. The pure S-enantiomer structure of landiolol is believed to develop less hypotensive side effects in comparison to other β-blockers. This has a positive impact on the treatment of patients when reduction of heart rate without decrease in arterial blood pressure is desired. It is used as landiolol hydrochloride.

The angiotensin receptor blockers (ARBs), also called angiotensin (AT1) receptor antagonists or sartans, are a group of antihypertensive drugs that act by blocking the effects of the hormone angiotensin II in the body, thereby lowering blood pressure. Their structure is similar to Ang II and they bind to Ang II receptors as inhibitors, e.g., [T24 from Rhys Healthcare].

<span class="mw-page-title-main">Complications of hypertension</span>

Complications of hypertension are clinical outcomes that result from persistent elevation of blood pressure. Hypertension is a risk factor for all clinical manifestations of atherosclerosis since it is a risk factor for atherosclerosis itself. It is an independent predisposing factor for heart failure, coronary artery disease, stroke, kidney disease, and peripheral arterial disease. It is the most important risk factor for cardiovascular morbidity and mortality, in industrialized countries.

Management of heart failure requires a multimodal approach. It involves a combination of lifestyle modifications, medications, and possibly the use of devices or surgery.

Preventive treatment of migraine can be an important component of migraine management. The goals of preventive therapy are to reduce the frequency, painfulness, and/or duration of migraine attacks, and to increase the effectiveness of abortive therapy. Another reason to pursue prevention is to avoid medication overuse headache (MOH), otherwise known as rebound headache, which can arise from overuse of pain medications, and can result in chronic daily headache. Preventive treatments of migraine include medications, nutritional supplements, lifestyle alterations, and surgery. Prevention is recommended in those who have headaches more than two days a week, cannot tolerate the medications used to treat acute attacks, or those with severe attacks that are not easily controlled.

<span class="mw-page-title-main">Celivarone</span> Experimental drug being tested for use in pharmacological antiarrhythmic therapy

Celivarone is an experimental drug being tested for use in pharmacological antiarrhythmic therapy. Cardiac arrhythmia is any abnormality in the electrical activity of the heart. Arrhythmias range from mild to severe, sometimes causing symptoms like palpitations, dizziness, fainting, and even death. They can manifest as slow (bradycardia) or fast (tachycardia) heart rate, and may have a regular or irregular rhythm.

<span class="mw-page-title-main">Sacubitril/valsartan</span> Combination medication

Sacubitril/valsartan, sold under the brand name Entresto, is a fixed-dose combination medication for use in heart failure. It consists of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan. The combination is sometimes described as an "angiotensin receptor-neprilysin inhibitor" (ARNi). In 2016, the American College of Cardiology/American Heart Association Task Force recommended it as a replacement for an ACE inhibitor or an angiotensin receptor blocker in people with heart failure with reduced ejection fraction.

<span class="mw-page-title-main">Fimasartan</span> Chemical compound

Fimasartan is a non-peptide angiotensin II receptor antagonist (ARB) used for the treatment of hypertension and heart failure. Through oral administration, fimasartan blocks angiotensin II receptor type 1 (AT1 receptors), reducing pro-hypertensive actions of angiotensin II, such as systemic vasoconstriction and water retention by the kidneys. Concurrent administration of fimasartan with diuretic hydrochlorothiazide has shown to be safe in clinical trials. Fimasartan was approved for use in South Korea on September 9, 2010, and is available under the brand name Kanarb through Boryung Pharmaceuticals, who are presently seeking worldwide partnership.

References

  1. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 Oct 2023.
  2. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 471. ISBN   9783527607495.
  3. 1 2 "Candesartan label" (PDF). FDA. February 2016. For label updates see FDA index page for IND 020838
  4. ↑ Cohn JN, Tognoni G (December 2001). "A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure". The New England Journal of Medicine. 345 (23): 1667–1675. doi: 10.1056/NEJMoa010713 . PMID   11759645.
  5. 1 2 Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, et al. (CHARM Investigators and Committees) (September 2003). "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. doi:10.1016/S0140-6736(03)14284-5. PMID   13678870. S2CID   5650345.
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  7. ↑ Julius S, Nesbitt SD, Egan BM, Weber MA, Michelson EL, Kaciroti N, et al. (April 2006). "Feasibility of treating prehypertension with an angiotensin-receptor blocker". The New England Journal of Medicine. 354 (16): 1685–1697. doi: 10.1056/NEJMoa060838 . PMID   16537662.
  8. ↑ Healey JS, Baranchuk A, Crystal E, Morillo CA, Garfinkle M, Yusuf S, Connolly SJ (June 2005). "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. doi: 10.1016/j.jacc.2004.11.070 . PMID   15936615.
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  10. ↑ Elkjaer AS, Lynge SK, Grauslund J (June 2020). "Evidence and indications for systemic treatment in diabetic retinopathy: a systematic review". Acta Ophthalmologica. 98 (4): 329–336. doi: 10.1111/aos.14377 . PMID   32100477. S2CID   211523341.
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  20. ↑ Cheungpasitporn W, Thongprayoon C, Chiasakul T, Korpaisarn S, Erickson SB (November 2015). "Renin-angiotensin system inhibitors linked to anemia: a systematic review and meta-analysis". QJM. 108 (11): 879–884. doi: 10.1093/qjmed/hcv049 . PMID   25697787. Open Access logo PLoS transparent.svg
  21. ↑ Patti R, Sinha A, Sharma S, Yoon TS, Kupfer Y (May 2019). "Losartan-induced Severe Hepatic Injury: A Case Report and Literature Review". Cureus. 11 (5): e4769. doi: 10.7759/cureus.4769 . PMC   6663042 . PMID   31363450.
  22. ↑ Torika N, Asraf K, Apte RN, Fleisher-Berkovich S (March 2018). "Candesartan ameliorates brain inflammation associated with Alzheimer's disease". CNS Neuroscience & Therapeutics. 24 (3): 231–242. doi:10.1111/cns.12802. PMC   6489976 . PMID   29365370.
  23. ↑ Saavedra JM (March 2016). "Evidence to Consider Angiotensin II Receptor Blockers for the Treatment of Early Alzheimer's Disease". Cellular and Molecular Neurobiology. 36 (2): 259–279. doi:10.1007/s10571-015-0327-y. PMID   26993513. S2CID   254384149.
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  25. ↑ Saavedra JM, Armando I, Bregonzio C, Juorio A, Macova M, Pavel J, Sanchez-Lemus E (June 2006). "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. doi: 10.1038/sj.npp.1300921 . PMID   16205776. S2CID   23912388.
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  27. ↑ Chen S, Ge Y, Si J, Rifai A, Dworkin LD, Gong R (Nov 2008). "Candesartan suppresses chronic renal inflammation by a novel antioxidant action independent of AT1R blockade". Kidney International. 74 (9): 1128–1138. doi: 10.1038/ki.2008.380 . PMID   18650791.
  28. ↑ Macconi D, Remuzzi G (2008). "Candesartan and renal protection: more than blocking angiotensin type 1 receptor?". Kidney International. 74 (9): 1112–1114. doi: 10.1038/ki.2008.420 .
  29. ↑ Mizuno K, Niimura S, Tani M, Saito I, Sanada H, Takahashi M, et al. (1992). "Hypotensive activity of TCV-116, a newly developed angiotensin II receptor antagonist, in spontaneously hypertensive rats". Life Sciences. 51 (20): PL183–PL187. doi:10.1016/0024-3205(92)90627-2. PMID   1435062.
  30. ↑ Ogihara T, Higashimori K, Masuo K, Mikami H (Jul–Aug 1993). "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. PMID   8221818.
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