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 diuretichydrochlorothiazide. 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]
Chemistry and pharmacokinetics
Candesartan is marketed as the
cyclohexyl 1-
hydroxyethylcarbonate (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
Candesartan is being investigated for its
neuroprotective and
anti-inflammatory properties. In an early
Alzheimer's diseasemouse model, candesartan significantly reduced
amyloid burden and inflammation[22] and is being examined as a potential treatment for early Alzheimer's.[23] Rat models show that candesartan may have neuroprotective benefits that ameliorate certain central mechanisms of
ageing and senescence.[24] Candesartan has also demonstrated some possible
therapeutic anti-stress and
anti-anxiety applications.[25] In a double-blind, placebo-controlled, randomized study, candesartan induced regression of
left ventricular hypertrophy, and improved LV function and exercise tolerance with no side effects in patients with non obstructive
hypertrophic cardiomyopathy.[26]
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.[27][28]
^
abGranger 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.
PMID13678870.
S2CID5650345.
^Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, et al. (September 2003). "Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme". Lancet. 362 (9386): 759–766.
doi:
10.1016/s0140-6736(03)14282-1.
PMID13678868.
S2CID15011437.
^Ducharme A, Swedberg K, Pfeffer MA, Cohen-Solal A, Granger CB, Maggioni AP, et al. (May 2006). "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.
doi:
10.1016/j.ahj.2005.06.036.
PMID16644318.
^
abcChaturvedi N, Porta M, Klein R, Orchard T, Fuller J, Parving HH, et al. (October 2008). "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.
doi:
10.1016/S0140-6736(08)61412-9.
PMID18823656.
S2CID20796943.
^
abcSjølie AK, Klein R, Porta M, Orchard T, Fuller J, Parving HH, et al. (October 2008). "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.
doi:
10.1016/S0140-6736(08)61411-7.
PMID18823658.
S2CID15210734.
^Stovner LJ, Linde M, Gravdahl GB, Tronvik E, Aamodt AH, Sand T, Hagen K (June 2014). "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.
doi:
10.1177/0333102413515348.
PMID24335848.
S2CID24678271.
^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.
PMID26993513.
S2CID254384149.
^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.
PMID1435062.
^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.
PMID8221818.