Candesartan

Article Author:
Kishen Bulsara
Article Editor:
Amgad Makaryus
Updated:
1/30/2019 7:49:54 AM
PubMed Link:
Candesartan

Indications

Candesartan is an oral angiotensin II receptor blocker. It is available as a pro-drug, candesartan cilexetil, which undergoes hydrolysis in the gastrointestinal tract during absorption to its active form. Candesartan is marketed under a variety of brand names.[1]

The FDA approved candesartan in June 1998 for the management of hypertension in adults. Based on clinical trials, a once-daily 8 mg dose of candesartan was shown to be as effective as a 50 mg dose of losartan, another angiotensin II receptor blocker, or a 10 to 20 mg dose of enalapril, an ACE inhibitor, in lowering blood pressure. The FDA also approved the use of candesartan to treat hypertension in adolescents and children aged one and older in October of 2009.[2],[3]

In February of 2005, the FDA approved the use of candesartan in adults with heart failure in New York Heart Association classes 2 to 4. The placebo-controlled CHARM studies have shown the efficacy of candesartan in these specific subpopulations:[4]

  • Patients with a left ventricular ejection fraction of 40% or less who have not previously tolerated ACE inhibitors
  • Patients with a left ventricular ejection fraction of 40% or less currently taking ACE inhibitors
  • Patients with a left ventricular ejection fraction of greater than 40%

The CHARM studies demonstrated a reduction in cardiovascular mortality and hospitalizations due to congestive heart failure, with either candesartan monotherapy or in combination with an ACE inhibitor.

Candesartan is also used off-label for the treatment of conditions including cerebrovascular accident or stroke,[5] diabetic nephropathy,[6] left ventricular hypertrophy,[7] and migraines.[8]

Candesartan is often prescribed as monotherapy for the management of hypertension and heart failure. However, a combination formulation exists with low-dose hydrochlorothiazide, a thiazide diuretic. This combination helps to achieve an additional antihypertensive effect.[9]

Mechanism of Action

Candesartan, like ACE inhibitors such as enalapril and direct renin inhibitors such as aliskiren, interferes with the renin-angiotensin-aldosterone system (RAAS). Normally, renin is released by renal juxtaglomerular cells in response to decreased renal perfusion pressure, increased sympathetic tone, and decreased delivery of sodium chloride to macula densa cells in the distal convoluted tubule of the nephron. Angiotensinogen, released by the liver, is cleaved into angiotensin I by renin. Angiotensin I is converted into angiotensin II in the lungs by the action of angiotensin-converting enzyme (ACE). Angiotensin II has several effects, including:

  • Binding to angiotensin II receptor type 1 in vascular smooth muscle, leading to vasoconstriction and increased blood pressure.
  • Constricting the efferent arteriole in the kidney, preserving glomerular filtration rate when renal perfusion drops.
  • Increasing the activity of the sodium-proton cotransporter in the proximal convoluted tubule of the nephron. This promotes the reabsorption of sodium, water, and bicarbonate.
  • Stimulating the secretion of aldosterone from the zona glomerulosa of the adrenal cortex. Aldosterone acts on alpha-intercalated cells in the collecting duct to promote proton secretion and urine acidification. Aldosterone also acts on principal cells in the collecting duct to drive sodium reabsorption and potassium excretion. Ultimately, this leads to water retention, increased intravascular volume, and increased blood pressure.
  • Promoting the release of antidiuretic hormone from the posterior pituitary gland, which acts on principal cells to increase water reabsorption via aquaporin-2 channels. This action raises the intravascular volume and increases blood pressure.

Candesartan works by antagonizing the angiotensin II receptor type 1. This blocks the aforementioned effects of angiotensin II and leads to a reduction in blood pressure and fluid retention. Since candesartan only blocks the binding of angiotensin II to its target receptor, its action is independent of the upstream steps leading to angiotensin II biosynthesis. An angiotensin II receptor type 2 also exists but it plays no role in the maintenance of blood pressure and normal hemodynamics. Furthermore, candesartan binds angiotensin II receptor type 1 10,000 times more strongly than it does type 2.[1],[3]

Administration

Candesartan is administered orally and is available as 4 mg, 8 mg, 16 mg, and 32 mg tablets. For patients who have difficulty swallowing, oral suspensions are available.

Specific Dosages

Hypertension:[2],[3]

  • Adults and geriatric patients should receive an initial dose of 16 mg once daily. If the patient is volume-depleted, the initial dose should be lowered to 8 mg once daily. Usual dose ranges from 8 to 32 mg/day.
  • Children and adolescents six years and older, weighing greater than 50 kg, should receive an initial dose of 8 to 16 mg once daily. If the patient is volume-depleted, the initial dose should be lowered to 4 mg once daily. The usual dose ranges from 4 to 32 mg/day.
  • Children and adolescents six years and older, weighing less than 50 kg, should receive an initial dose of 4 to 8 mg once daily. If the patient is volume-depleted, the initial dose should be lowered to 2 mg once daily. The usual dose ranges from 2 to 16 mg/day.
  • Children between one and six years old should receive an initial dose of 0.2 mg/kg/day as an oral suspension. If the patient is volume-depleted, the initial dose should be lowered to 0.1 mg/kg/day. The usual dose ranges from 0.05 to 0.4 mg/kg/day.

Heart failure: Adults should receive 4 to 8 mg once daily.[4]

Migraine prophylaxis: Adults should receive 16 mg once daily.[8]

Adverse Effects

The most common adverse effects reported for candesartan are symptomatic hypotension, abnormal renal function, and hyperkalemia. In the CHARM program, symptomatic hypotension, impaired renal function (rise in creatinine), and hyperkalemia were seen with an incidence of 18.8%, 12.5%, and 6.3%, respectively. Hypotension is most commonly seen in patients who are volume- or salt-depleted secondary to dietary restriction, dialysis, diarrhea, emesis, or diuretic use.[4]

Other reported side effects include a headache, back pain, angioedema, and upper respiratory tract infections, but these are very rarely observed clinically.

Candesartan is considered a teratogen and has a black box warning for fetal toxicity. If used in the second or third trimesters of pregnancy, medications that interfere with the renin-angiotensin-aldosterone system diminish fetal renal function. An increased risk of morbidity and death secondary to oligohydramnios results from decreased renal function. These neonates may develop skull hypoplasia, lung hypoplasia, hypotension, renal failure, and may ultimately expire.[10],[11]

Contraindications

The only major contraindication to candesartan is hypersensitivity to the medication or any of its components.

Monitoring

Patients taking candesartan should have their blood pressure routinely measured to assess for adequate blood pressure response to the medication. Additionally, patients should be monitored for adverse effects of symptomatic hypotension including dizziness, lightheadedness, nausea, syncope, and fatigue.[12] 

Hyperkalemia and impaired renal function are seen with candesartan use. Therefore, the serum potassium and renal function should periodically be monitored.[13]

Toxicity

Candesartan overdose would most likely manifest as symptomatic hypotension, dizziness, and reflexive tachycardia. Patients who develop symptomatic hypotension should have their vital signs monitored. Patients should be instructed to lie down supine and raise their legs. If this is insufficient, fluid resuscitation and/or supportive pharmacotherapy may be initiated to increase the blood pressure.[12] 

Enhancing Healthcare Team Outcomes

Candesartan is an antihypertensive agent that is also used to manage congestive heart failure. The drug is effective but prescribers need to be aware of its side effects. Candesartan overdose would most likely manifest as symptomatic hypotension, dizziness, and reflexive tachycardia. Patients who develop symptomatic hypotension should have their vital signs monitored. Patients should be instructed to lie down supine and raise their legs. If this is insufficient, fluid resuscitation and/or supportive pharmacotherapy may be initiated to increase the blood pressure.[12] 


References

[1] Gohlke P,Jürgensen T,von Kügelgen S,Unger T, Candesartan cilexetil: development and preclinical studies. Drugs of today (Barcelona, Spain : 1998). 1999 Feb     [PubMed PMID: 12973413]
[2] Zhao D,Liu H,Dong P, A Meta-analysis of antihypertensive effect of telmisartan versus candesartan in patients with essential hypertension. Clinical and experimental hypertension (New York, N.Y. : 1993). 2018 Mar 28     [PubMed PMID: 29589977]
[3] Sever P, Candesartan cilexetil: a new, long-acting, effective angiotensin II type 1 receptor blocker. Journal of human hypertension. 1997 Sep     [PubMed PMID: 9331018]
[4] Lund LH,Claggett B,Liu J,Lam CS,Jhund PS,Rosano GM,Swedberg K,Yusuf S,Granger CB,Pfeffer MA,McMurray JJV,Solomon SD, Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum. European journal of heart failure. 2018 Feb 12     [PubMed PMID: 29431256]
[5] Fu H,Hosomi N,Pelisch N,Nakano D,Liu G,Ueno M,Miki T,Masugata H,Sueda Y,Itano T,Matsumoto M,Nishiyama A,Kohno M, Therapeutic effects of postischemic treatment with hypotensive doses of an angiotensin II receptor blocker on transient focal cerebral ischemia. Journal of hypertension. 2011 Nov     [PubMed PMID: 21934531]
[6] Takao T,Horino T,Kagawa T,Matsumoto R,Shimamura Y,Ogata K,Inoue K,Taniguchi Y,Taguchi T,Morita T,Terada Y, Possible involvement of intracellular angiotensin II receptor in high-glucose-induced damage in renal proximal tubular cells. Journal of nephrology. 2011 Mar-Apr     [PubMed PMID: 20890878]
[7] Wang Z,Niu Q,Peng X,Li M,Liu K,Liu Y,Liu J,Jin F,Li X,Wei Y, Candesartan cilexetil attenuated cardiac remodeling by improving expression and function of mitofusin 2 in SHR. International journal of cardiology. 2016 Jul 1     [PubMed PMID: 27085127]
[8] Fehér G,Pusch G, [Role of antihypertensive drugs in the treatment of migraine]. Orvosi hetilap. 2015 Feb 1     [PubMed PMID: 25618859]
[9] Hosaka M,Metoki H,Satoh M,Ohkubo T,Asayama K,Kikuya M,Inoue R,Obara T,Hirose T,Imai Y, Randomized trial comparing the velocities of the antihypertensive effects on home blood pressure of candesartan and candesartan with hydrochlorothiazide. Hypertension research : official journal of the Japanese Society of Hypertension. 2015 Oct     [PubMed PMID: 26041602]
[10] Korkes H,Oliveira LG,Berlinck L,Borges AF,Goes FS,Watanabe S,Landman C,Sass N, PP138. Human fetal malformations associated with the use of angiotensin II receptor antagonist. Pregnancy hypertension. 2012 Jul     [PubMed PMID: 26105460]
[11] Hünseler C,Paneitz A,Friedrich D,Lindner U,Oberthuer A,Körber F,Schmitt K,Welzing L,Müller A,Herkenrath P,Hoppe B,Gortner L,Roth B,Kattner E,Schaible T, Angiotensin II receptor blocker induced fetopathy: 7 cases. Klinische Padiatrie. 2011 Jan     [PubMed PMID: 21271514]
[12] Prasa D,Hoffmann-Walbeck P,Barth S,Stedtler U,Ceschi A,Färber E,Genser D,Seidel C,Deters M, Angiotensin II antagonists - an assessment of their acute toxicity. Clinical toxicology (Philadelphia, Pa.). 2013 Jun     [PubMed PMID: 23692319]
[13] Desai AS,Swedberg K,McMurray JJ,Granger CB,Yusuf S,Young JB,Dunlap ME,Solomon SD,Hainer JW,Olofsson B,Michelson EL,Pfeffer MA, Incidence and predictors of hyperkalemia in patients with heart failure: an analysis of the CHARM Program. Journal of the American College of Cardiology. 2007 Nov 13     [PubMed PMID: 17996561]