Candesartan is an angiotensin II receptor blocker used widely in the therapy of hypertension and heart failure. Candesartan is associated with a low rate of transient serum aminotransferase elevations and has been linked to rare instances of acute liver injury.
Candesartan (kan" de sar' tan) is an angiotensin II receptor blocker (ARB) that is widely used alone or in combination with other agents as therapy of hypertension and heart failure. Candesartan inhibits the renin-angiotensin system by blocking the angiotensin II type 1 receptor (AT1), which prevents the vasoconstriction and volume expansion induced by circulating angiotensin II, accounting for its antihypertensive activity. Candesartan was approved for use in the United States in 1998 and is available in 4, 8, 16 and 32 mg tablets generically and under the trade name Atacand. Current indications include treatment of hypertension (usually in combination with other agents) and to prevent cardiovascular events and death in patients with chronic heart failure. The typical dose of candesartan in adults is 16 to 32 mg once daily, and it is used long term. Candesartan is also available in fixed combinations with hydrochlorothiazide (Atacand HCT and others). Side effects of candesartan are uncommon, but may include headache, dizziness, fatigue, cough, gastrointestinal upset and fetal toxicity. Many ARBs, but not specifically candesartan, have been linked to cases of a severe sprue-like enteropathy that presents with severe diarrhea and weight loss and villous flattening and atrophy on intestinal biopsy arising after months or years of ARB use. The enteropathy resembles celiac disease but does not repond to a gluten-free diet, but resolves promptly with stopping the angiotensin receptor blocker.
Candesartan has been associated with a low rate of serum aminotransferase elevations (<1%) that in controlled trials was no higher than with placebo therapy. These elevations were transient and rarely required dose modification. Rare instances of clinically apparent acute liver injury have been reported in association with candesartan therapy. The onset is usually within 1 to 8 weeks of starting therapy and the serum enzyme pattern can be either hepatocellular or cholestatic with an acute hepatitis- or cholestatic hepatitis-like clinical syndrome. In some instances, cholestasis can be prolonged and relapsing, but candesartan therapy has not been associated with vanishing bile duct syndrome or chronic liver injury. Immunoallergic manifestations (rash, fever, eosinophilia) are not common, nor is autoantibody formation.
Likelihood score: C (Probable cause of rare instances of clinically apparent liver injury).
Mechanism of Injury
The cause of the minor serum aminotransferase elevations and the acute liver injury associated with candesartan is not known, but resembles idiosyncratic liver injury due to a hypersensitivity reaction. Candesartan has minor liver metabolism through the cytochrome P450 system (CYP 2C9) and has minimal drug-drug interactions.
Outcome and Management
The instances of acute liver injury reported with candesartan use have been self limited and have not resulted in acute liver failure or chronic liver injury. While corticosteroids have been used in cases of severe cholestasis due to ARBs, their efficacy has not been shown and their use is best avoided. Patients with candesartan induced acute liver injury should probably avoid use of other ARBs, although cross sensitivity to liver injury among the members of this class of agents has not been shown.
References on the safety and potential hepatotoxicity of candesartan are given in the Overview section on the angiotensin II receptor antagonists.
Other Drugs in the Subclass, Angiotensin II Receptor Antagonists: Azilsartan, Eprosartan, Irbesartan, Losartan, Olmesartan, Telmisartan, Valsartan
Case 1. Severe hepatitis attributed to candesartan.
[Modified from: Basile G, Villari D, Gangemi S, Ferrara T, Accetta MG, Nicita-Mauro V. Candesartan cilexetil-induced severe hepatotoxicity. J Clin Gastroenterol 2003; 36: 273-5. PubMed Citation]
|Medication:||Candesartan (16 mg daily)|
|Severity:||4+ (jaundice, prothrombin time prolongation and ascites)|
|Other medications:||None mentioned|
|Weeks After Starting||Weeks After Stopping||ALT (U/L)||Alk P (U/L)||Bilirubin (mg/dL)||Other|
|DRUG||CAS REGISTRY NUMBER||MOLECULAR FORMULA||STRUCTURE|