Possible Mechanisms of Nitrate Tolerance Uri Elkayam,

MD,

Anil Mehra,

MD,

Avraham Shotan,

Prolonged exposure to organic nitrates has been !zihomtoleadtotherapkldevekpmentoftolerante to the peripheral and -WV-W efbctsofthesedrugs.AsaresuItofthlsphenamenon, the hemodynamk and anti-lsdwmk effect8ofnltratesmayberapldlyattenuatedIn patlentswtthlschemkheartdlsease,cangesthre heart faibre, or both. lids nitrate tokrance appeatstobebothdose-andthne-dependent. Ukelymechanlsmsproposedforltsdevelopment are multlfactobial and inch& depktk~ of suIfhymedlabdhweaseinblood W imw, a nbb+ volume, and nau robmmml stlmulatkn wlth actlvatlonofv~hfemechanlsms. (Am J Cawllol1992;7&49SS4G)

From the Department of Medicine, Division of Cardiology, University of Southern California (USC) Los Angeles, California. Address for reprints: Uri Elkayam, MD, Division of Cardiology, USC School of Medicine, 2025 Zonal Avenue, Los Angeles, California 90033.

MD,

Enrique Osprzega,

MD

T

he rapid development of tolerance with prolonged exposure to organic nitrates is well documented in the scientific literature. Nitroglycerin tolerance was described as early as 1905 by Steward,’ who expressed frustration at an inability to overcome tolerance to the drug, despite a 160-fold increase in the nitrate dose level. The development of immunity to the undesirable side effects of nitroglycerin, particularly headache, within 3-4 days by workers engaged in its manufacture further suggested nitrate tolerance.2 This immunity was lost rapidly, as indicated by the reappearance of symptoms of nitroglycerin toxicity after an absence from work of only a few days. For this reason, it became common practice for nitroglycerin workers to place some of the product in their hatbands during periods of absence from the factory so as to maintain their immunity. Thus as early as 1914 the importance of intermittent exposure to nitrates for the maintenance of the drug effect was being recognized.2 A recent review of data from 22 studies conducted between 1980 and 1989 provided strong evidence for the development of nitrate tolerance in patients with angina pectoris.3 These patients were treated with various types of nitrate preparations, including standard and sustained-release oral formulations, transdermal systems, and intravenous formulations, for periods ranging from 1 day to 2 months. Despite considerable data supporting the occurrence of nitrate tolerance, its clinical importance has been questioned in the past. This earlier skepticism was attributable to findings such as those of Danahy and Aronow.4 These investigators conducted treadmill exercise tests in 21 men with typical effort angina 1, 3, and 5 hours after an initial oral dose of isosorbide dinitrate (ISDN) or placebo. Exercise performance at all 3 evaluation periods was enhanced in the ISDN-treated patients compared with placebo. When the researchers repeated exercise testing after a mean of 5.6 months of treatment with ISDN, they found that the antianginal effect of the drug was maintained. Careful examination of the protocol followed in this study, however, revealed that patients were A SYMPOSIUM:

OPTIMIZING

ANTIANGINAL

THERAPY

49G

allowed a 16-hour nitrate-free interval prior to the reevaluation of ISDN effect. Similarly, a period of nitrate withdrawal was also used by Franciosa and Cohn5 who reported persistence of the hemodynamic effect of ISDN in patients with congestive heart failure. Nevertheless, the information available in the early 1980s led to the conclusion that prolonged therapy with long-acting nitrates was not associated with clinically important tolerance, even when these agents were used in large doses.‘j MANIFESTA~ONS OF NITRATE TOLERANCE There are other data, however, to support the rapid and marked attenuation of all aspects of nitrate activity, including effects on the peripheral and coronary circulation and on platelet activity, with continuous exposure or frequent dosing. Effect on peripheral circulation: A 1985 study by Manyari et al7 demonstrated a significant increase in regional blood volume, measured by the radionuclide blood pool method, in patients with stable angina after an initial dose of 0.6 mg of sublingual glyceryl trinitrate. After 4 weeks of treatment with ISDN, the response to glyceryl trinitrate was markedly attenuated (Figure 1). The earlier changes in blood pressure and heart rate achieved with glyceryl trinitrate were also signifi-

n

m.=.9 Stage A

-

Stage B

-6-4-2

2

0

4

6

10

Time (min) FWURE l. Changes In regional blood volume In msponse -7---------

-------

--

----------

-

-------

---

(IBDN, stage B). Patients received 0.6 mg of subllmal nHto&cedn attlnm0. *p

Possible mechanisms of nitrate tolerance.

Prolonged exposure to organic nitrates has been shown to lead to the rapid development of tolerance to the peripheral and coronary vasodilatory effect...
844KB Sizes 0 Downloads 0 Views