Are there any known pharmacological interactions between warfarin and candesartan?/nA 57-year-old w

Fråga: Are there any known pharmacological interactions between warfarin and candesartan?

A 57-year-old woman with membranous nephropathy was treated with warfarin for peripheral and cerebral venous thromboses. One week after starting antihypertensive treatment with candesartan, she was admitted to hospital with arthralgia, fever, facial edema and alveolitis. She was treated with steroids, antihistamines and antibiotics. Subsequently, she was diagnosed with a large intramuscular hematoma and her INR (International Normalized Ratio) was found to be 6.0 (therapeutic interval approximately 2-3). She also had hypoalbuminemia with an albumin concentration of 19 g/L (reference interval 34-44 g/L). The patient was then treated with vitamin K and the INR fell to 1.3. Shortly thereafter, she developed a cerebral infarction and died from increased intracranial pressure.

The case has been reported to the regional pharmacovigilance centre.

Sammanfattning: There are no reports of interactions between candesartan and warfarin, and there is even some empiric evidence that candesartan does not alter the effects of warfarin. Theoretically, the inflammatory state induced in this patient could have caused down-regulation of drug-metabolising enzymes, thereby reducing the elimination of warfarin. Also, possible interactions between warfarin and the medication given after admission to hospital should be considered.

Svar: The majority of known pharmacological interactions with warfarin involve inhibition of its metabolism, most commonly by inhibition of the cytochrome P450 isoenzyme CYP2C9 that metabolises the more potent S-enantiomer of racemic warfarin (1). CYP2C9 is involved in the metabolism of candesartan (2), but no positive reports of interactions between the two substances were found in Medline, Drugline or standard pharmacological literature. On the contrary, it has been demonstrated that ten days´ addition of candesartan to a stable warfarin therapy does not interfere with the latter (3). This is in coherence with the finding that CYP2C9 enzymatic activity in vitro is virtually unaltered by therapeutic concentrations of candesartan (4).

In the present case, hypoalbuminemia was noted. This condition is, however, not expected to alter the pharmacokinetics of warfarin, since albumin loss is a relatively slow process. If such a decline in albumin concentration were to evolve from decreased synthesis in the liver, albumin´s biological half-life of 17 to 20 days would make the decline too slow to cause an increase in unbound warfarin concentration (5). Even if the mechanism would involve renal dysfunction with increased loss of albumin, it appears unlikely that the decline rate would be high enough to match the half-life of the more potent S-warfarin enantiomer (18-65 h) (6). Furthermore, there is no evidence that the hypoalbuminemia in the present case was not present prior to the candesartan treatment. Rather, it seems plausible that it was caused by the preexisting nephropathy and, if so, had been present for a longer period of time.

Another mechanism by which an interaction could possibly arise is altered warfarin metabolism secondary to the allergic/inflammatory reactions caused by candesartan. Several inflammatory mediators have an inherent potency to down-regulate the expression of different drug biotransformation enzymes. However, the exact mechanisms and the applicability to warfarin remain to be elucidated (7).

There are no obvious reasons to expect any pharmacodynamic interactions between candesartan and warfarin.

Lastly, interactions between warfarin and the other medication given (steroids, antihistamines and antibiotics) should be considered. 1 Sjöqvist F. Interaktion mellan läkemedel. In: FASS 2003 (The Swedish catalogue of approved medical products). p. 1694-1778. 2 Produktresume Atacand 3 Stockley IH. Drug interactions. 6th ed. London: The Pharmaceutical Press; 2002. p. 386. 4 Hanatani T, Fukuda T, Ikeda M, Imaoka S, Hiroi T, Funae Y, Azuma J. CYP2C9*3 influences the metabolism and the drug-interaction of candesartan in vitro. Pharmacogenomics J 2001;1:288-92. 5 Fauci AS, Braunwald E, Isselbacher KJ, Wilson JD, Martin JB, Kasper DL, Hauser SL, Longon DL (eds), Harrison´s, Principles of internal medicine. 14th ed. New York: McGraw-Hill Inc; 1998. p. 1669. 6 Dollery C Sir, editor. Therapeutic drugs. 2nd ed. Edinburgh: Churchill Livingstone; . 1999. p. W1. 7 Renton KW. Alteration of drug biotransformation and elimination during infection and inflammation. Pharmacol Ther 2001;92:147-63.