Bernice Farrell

Effect of Intervals between Doses on the Development of Tolerance to Isosorbide Dinitrate

We studied the development of tolerance to isosorbide dinitrate in 12 patients with chronic stable angina pectoris. The effect of 30 mg of isosorbide dinitrate on treadmill exercise performance was assessed before and at one, three, and five hours after a single dose. As compared with placebo, the drug increased treadmill walking time until the onset of angina and until the development of moderate angina over the five-hour observation period (P less than 0.05). The patients then received 30 mg of isosorbide dinitrate twice, three times, and four times daily for a period of one week, and exercise performance was assessed before and at one, three, and five hours after the final morning dose. During sustained treatment two and three times daily, treadmill walking time was longer throughout the five-hour testing period than during the placebo phase (P less than 0.05). In contrast, during treatment four times daily, treadmill walking time was prolonged at one hour (P less than 0.05) but not at three and five hours after the last dose. We conclude that tolerance to the clinical effects of isosorbide dinitrate develops with a sustained dosage of 30 mg four times daily, but not when the drug is given two or three times daily.

Nitrate tolerance: the lack of effect of N-acetylcysteine.

The hemodynamic and antianginal effects of 30 mg of isosorbide dinitrate (ISDN) were assessed in 12 patients with chronic stable angina after initial dosing and after 7 to 10 days of therapy four times daily. During early therapy, ISDN produced significant hemodynamic and antianginal effects that persisted over a 3 hr observation period. During sustained therapy there was attenuation of the hemodynamic effects at rest, and treadmill exercise time to the onset of angina and to the development of moderate angina was increased 1 hr after dosing; no effect was apparent at 3 hr. During this state of nitrate tolerance, patients were treated with an infusion of normal saline or 100 mg/kg N-acetylcysteine and exercise testing was repeated. N-Acetylcysteine did not change the hemodynamic findings at rest or during exercise and there was no improvement in exercise tolerance. It is apparent that the short-term administration of reduced sulfhydryl groups does not reverse tolerance to the hemodynamic and antianginal effects of isosorbide dinitrate in an exercise test model.

Nitroglycerin lingual spray: Clinical efficacy and dose-response relation

Twenty patients with chronic, stable, exercise-induced angina pectoris were studied after receiving lingual sprays that delivered 0.2, 0.4 and 0.8 mg of nitroglycerin (GTN). The hemodynamic effects and changes in exercise time to the onset of angina and to the development of moderate angina were compared with those of placebo spray and 0.4 mg of sublingual GTN. A dose-response relation was apparent with the 3 doses of active spray for heart rate at rest but not for standing systolic blood pressure. Sublingual GTN produced effects similar to those with 0.4 and 0.8 mg of GTN spray, but exceeded the response to 0.2 mg of GTN spray. Treadmill walking time to the onset of angina and to the development of moderate angina was prolonged with each dose of GTN spray and showed a dose-response relation with significantly greater effects with increasing doses of GTN spray. This study indicates that GTN lingual spray is effective in the prophylaxis of angina and should be effective in the therapy of exercise-induced or spontaneous episodes of angina pectoris. The dose of 0.4 or 0.8 mg would appear to be most effective and similar to 0.4 mg of sublingual GTN.

Comparison of buccal nitroglycerin and oral isosorbide dinitrate for nitrate tolerance in stable angina pectoris

Sixteen patients with chronic stable angina pectoris were studied to compare the hemodynamic and antianginal effects of buccal nitroglycerin (GTN) in a dose of 3 mg administered 3 times daily and oral isosorbide dinitrate (ISDN) in a dose of 30 mg administered 4 times daily. Compared with placebo, both oral ISDN and buccal GTN treatment induced a decrease in systolic blood pressure at rest over a 5-hour period during acute but not during sustained therapy. Neither buccal GTN nor oral ISDN modified the changes in systolic blood pressure during exercise. Both treatment programs were associated with a higher exercise heart rate during acute therapy. During sustained treatment with buccal GTN, the heart rate during exercise remained greater than that during placebo throughout the 5-hour test period, but during treatment with oral ISDN, only the exercise heart rate at 1 hour was greater than that seen with placebo. Treadmill walking time to the onset of angina and to the development of moderate angina increased significantly during acute therapy with both buccal GTN and oral ISDN. The clinical efficacy of buccal GTN was maintained after 2 weeks of 3-times-daily therapy. In contrast, during 4-times-daily therapy with oral ISDN, treadmill walking time was prolonged for only 1 hour after drug administration. This investigation indicates that tolerance develops during 4-times-daily therapy with oral ISDN, but 3 times daily therapy with buccal GTN is not associated with diminished antianginal effects.

The effect of supplemental L-arginine on tolerance development during continuous transdermal nitroglycerin therapy

OBJECTIVES This study was designed to assess the effect of oral L-arginine on the development of tolerance during continuous transdermal nitroglycerin (TD-GTN) therapy. BACKGROUND Continuous TD-GTN therapy leads to complete tolerance within 24 to 48 h. The mechanism(s) responsible for nitrate tolerance are unclear, but there is increasing evidence that nitroglycerin (GTN) leads to superoxide anion production. The trigger for this is unknown, but there is evidence that GTN alters nitric oxide synthase (NOS) function and also leads to reduced L-arginine availability at its site of action with NOS. METHODS Fourteen patients with stable angina pectoris and reproducible treadmill walking time (TWT) until the onset of moderate angina were studied in a placebo-controlled, crossover study. Transdermal GTN (0.4 mg/h) was applied daily for two periods of 5 to 10 days with the patch left in place for 24 h each day. Capsules containing L-arginine (700 mg) or placebo were administered four times daily during a period of TD-GTN therapy. Treadmill walking time was determined before and 4 h after study capsules on day 1 before TD-GTN to assess the effect of L-arginine on exercise performance. On the last day, TWT was determined at 0 h (24 h after TD-GTN and 9 h after study capsule) and 4 h after TD-GTN reapplication and study capsule. After a 5 to 10 day washout period, the study was repeated with the opposite study capsule. RESULTS Treadmill walking time until the onset of moderate angina was not influenced by the short-term administration of L-arginine. During continuous TD-GTN, the administration of L-arginine increased TWT 4 h and 24 h after patch application. This was significantly greater than TWT during administration of placebo capsules (p < 0.05). CONCLUSIONS The administration of L-arginine modified or prevented the development of nitrate tolerance during continuous TD-GTN therapy.

Intermittent transdermal nitroglycerin therapy; Decreased anginal threshold during the nitrate-free interval

BACKGROUND Intermittent transdermal nitroglycerin therapy is effective in the treatment of stable angina and prevents the development of tolerance. Previous investigations have suggested that removal of nitroglycerin patches may be associated with a decrease in anginal threshold. This study examines the effect of nitroglycerin patch removal on anginal threshold in a group of patients with stable angina. METHODS AND RESULTS Twelve patients with stable angina were enrolled in a randomized, double-blind, placebo-controlled, crossover study. These patients had reproducible treadmill walking times and were taking no other long-acting antianginal medications or vasodilators. They received 0.8 mg/h transdermal nitroglycerin or wore a matching placebo patch for 5 to 7 days and then crossed over to the other treatment arm of the study. Transdermal nitroglycerin was applied at 8:00 PM and removed at 8:00 AM each day. On the last day of each treatment period, patients underwent treadmill exercise testing at 8:00 AM (before patch removal) and at 2, 4, and 6 hours after patch removal. The primary end point was the treadmill walking time until moderate angina (P2). Other end points included the treadmill walking time until onset of angina (P1), the amount of ST segment depression at P1 and P2, and treadmill walking time until the development of 1 mm ST depression. Heart rate, systolic blood pressure, and the rate-pressure product were determined at rest before exercise and at P1 and P2. At 8:00 AM P1 and P2 were not significantly affected by active nitroglycerin compared with placebo, indicating the development of tolerance. Removal of the active transdermal nitroglycerin patch was associated with a significant decrease in the time to P1 at 2, 4, and 6 hours after patch removal compared with placebo. There was also a decrease in the time to P2 after active patch removal that was statistically significant compared with placebo at 2 and 4 hours and was of borderline significance at 6 hours. There were no differences in heart rate, blood pressure, or amount of ST segment depression at either P1 or P2 after active compared with placebo patch removal. CONCLUSIONS In patients with stable angina pectoris, intermittent transdermal nitroglycerin therapy is associated with a decrease in anginal threshold for 4 to 6 hours after patch removal. Although the cause of this phenomenon remains uncertain, it may be due to counterregulatory responses that develop during nitroglycerin patch application.

Effects of diuretic therapy on the development of tolerance during continuous therapy with nitroglycerin

OBJECTIVES This study examined the effects of concurrent diuretic therapy on the hemodynamic responses to short-term and sustained therapy with transdermal nitroglycerin. BACKGROUND Sodium retention and plasma volume expansion occur during therapy with nitroglycerin and may play a role in the loss of nitroglycerin effects during sustained therapy. METHODS Twenty-two normal male volunteers were treated for 1 week with either hydrochlorothiazide and amiloride (50 + 5 mg) (n = 11) or placebo (n = 11) in a randomized, double-blind fashion. All 22 subjects then received continuous transdermal nitroglycerin (19 +/- 1 mg/24 h) for 5 to 7 days. RESULTS On the first and last day of transdermal nitroglycerin therapy, standing heart rate, systolic blood pressure and hematocrit values were assessed at 8, 9 and 10 AM and 12 noon. Heart rate and blood pressure responses to sublingual nitroglycerin (0.6 mg) were also evaluated before and after sustained transdermal nitroglycerin therapy. A significant loss of the hemodynamic effects of transdermal and sublingual nitroglycerin occurred during sustained therapy in both the diuretic and placebo therapy groups. In both groups, transdermal nitroglycerin therapy was associated with a significant decrease in hematocrit that persisted for the entire treatment period. CONCLUSIONS These results suggest that diuretic therapy does not prevent plasma volume expansion or the loss of hemodynamic effects during sustained transdermal nitroglycerin therapy. The persistent decrease in hematocrit suggests that plasma volume expansion plays a role in the attenuation of nitrate effects. It also provides evidence of continued vascular activity of nitroglycerin despite loss of systemic hemodynamic effects.

Effects of Diuretic Therapy on the Development of Tolerance to Nitroglycerin and Exercise Capacity in Patients With Chronic Stable Angina

BACKGROUND Therapy with diuretics has been reported to prevent the development of nitrate tolerance. Importantly, diuretics may have independent antianginal effects through their effects on intravascular volume. The present investigation was designed to determine whether diuretic therapy could prevent the development of tolerance to continuous transdermal nitroglycerin. The study was also designed to examine whether diuretic therapy has an independent antianginal effect. METHODS AND RESULTS Twelve patients with chronic stable angina were studied in a randomized, double-blind, crossover trial. Patients received diuretic (hydrochlorothiazide plus amiloride) or placebo for 14 to 20 days. During each double-blind treatment period, patients underwent treadmill exercise testing on three separate occasions. The first exercise testing was performed after 7 to 10 days of single-blind, placebo transdermal nitroglycerin therapy. Subsequently, exercise testing was repeated on the first day of active transdermal nitroglycerin therapy and following 7 to 10 days of continuous transdermal nitroglycerin application. Therapy with a diuretic was associated with an increase in exercise capacity but had no effect on nitroglycerin tolerance. During therapy with placebo transdermal nitroglycerin, diuretic therapy caused an increase in treadmill walking time to the development of moderate angina compared with placebo (371 +/- 26 versus 288 +/- 16 seconds, diuretic versus placebo, P < .01). Similar results were obtained during both acute and sustained nitroglycerin therapy. CONCLUSIONS The results of this study demonstrate that therapy with a diuretic has no effect on the development of tolerance to continuous transdermal nitroglycerin. Interestingly, diuretic therapy itself has important antianginal effects and improves exercise capacity in patients with stable angina.

Comparative antianginal effects of bepridil and propranolol in angina pectoris

Eighteen patients with chronic, stable angina were studied in a double-blind, placebo-controlled, 3-way, crossover study in which they received 4 weeks of treatment with a once-daily dose of bepridil, 300 mg, a once-daily dose of long-acting propranolol, 160 mg, and placebo. Heart rate at rest during bepridil treatment was less than that during placebo (p less than 0.01), whereas propranolol reduced heart rate compared with placebo (p less than 0.001) and bepridil (p less than 0.01). Systolic blood pressure at rest did not change during the 3 treatment phases. Exercise time to onset of angina and to development of moderate angina were reproducible over the 24-hour period during each treatment phase. Treadmill walking time to onset of angina and to development of moderate angina was significantly prolonged during bepridil (p less than 0.01) and during propranolol treatment (p less than 0.05). Heart rate at peak exercise was similar during bepridil and during placebo, but was markedly reduced with propranolol treatment (p less than 0.001). Systolic blood pressure during exercise was similar during placebo and bepridil, but was substantially lower during propranolol treatment (p less than 0.01).