HIGH-DOSE TRANSDERMAL NITROGLYCERIN TREATMENT - ATTENUATED ACTION WITHIN 24 HOURS

  • 1 January 1985
    • journal article
    • research article
    • Vol. 10  (3) , 157-162
Abstract
Within a relatively short period of time, nitroglycerin patches have come into widespread use for treatment of coronary artery disease in the absence of sufficient clinical data in support of their efficacy. Presently, there is still considerable controversy regarding the extent and duration of action as well as the dosage requirement. Six patients with angiographically-documented coronary artery disease, stable exercise-induced angina pectoris and reproducible ST-segment depression were studied to analyze the effects of nitroglycerin patches formulated to deliver 5 mg, 10 mg, 20 mg as well as 30 mg per 24 h, respectively, on the extent of ST-segment depression. The extent and duration of antianginal and anti-ischemic effects of nitroglycerin patches delivering 30 mg/24 h were investigated in 10 patients according to a randomized, double-blind, crossover placebo-controlled protocol. In 7 of these patients, testing was again performed at 2.5 h after repeated application (2nd application at 24 h). Nitroglycerin patches delivering 5 mg, 10 mg, 20 mg as well as 30 mg/24 h respectively, led to significant reductions in ST-segment depression at 2.5 h of 59% (range 25-100%; P < 0.025), 63% (0-100%, P < 0.01), 77% (50-100%, P < 0.001) as well as 82% (50-100%, P < 0.005) as compared with control values (Figure 2). At 2.5 h after administration of nitroglycerin patches delivering 30 mg/24 h, all 10 patients demonstrated a significant mean reduction in ST-segment depression from 1.75 mm .+-. 0.13 (SEM[standard error of the mean]) to 0.20 .+-. 0.08 (89%; P < 0.001); the exercise capacity to onset of 1 mm ST-segment depression increased from 230 watt .times. min .+-. 39 to 559 watt .times. min .+-. 80 (143%; P < 0.001). AT 8 h there was a mean reduction in ST-segment depressin from 1.85 mm .+-. 0.15-1.3 mm .+-. 0.25 (30%; P < 0.025) but, at this time, 4 of the 10 patients already had a complete loss of effects; the exercise capacity to onset of 1 mm ST-segment depression was increased from 216 watt .times. min .+-. 42 to 321 wat .times. min .+-. 50 (49%; P < 0.05). At 24 h, there were no significant effects on either of the parameters. At 2.5 h after repeated patch application, no significant effects on mean ST-segment depression were observed; 4 of 7 demonstrated complete loss of effects, 3 of 7 showed an attenuated effect of 25-42% as compared to initial application. There was no significant change in the mean exercise capacity of 1 mm ST-segment depression (Figures 3 to 5). Nitroglycerin patches are effective at 2.5 h after the initial application; in general, higher doses elicit more marked effects. A persistent action over 24 h was not documented with patches delivering 30 mg. As compared with the initial application, repeated application after 24 hours was associated with a loss of, or attenuated effects. The cause of the rapidly attenuated or lost effects is assumed to be tolerance development. At the present time, no uniform clinical results with patches delivering lower doses were reported on which therapeutic recommendations can be based. Should a reliable anti-ischemic effect be documented for lower doses over a period of 8-10 h as well as after a nightly treatment pause with the effect of repeated application comparable to that seen after initial application, the possibility may exist to enable an effective long-term treatment with transdermal nitroglycerin provided that a nitrate-free interval is taken into consideration. On the use of high-dose treatment, however, rapid tolerance development with marked attenuation of effects within 8 h after the initial application must be assumed.

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