Ho-Leung Fung

Oral Isosorbide dinitrate in angina pectoris: Comparison of duration of action and dose-response relation during acute and sustained therapy

The effects of different oral doses of isosorbide dinitrate administered acutely and four times daily during sustained therapy were studied in 12 patients with angina pectoris. After administration of 30, 60 and 120 mg of isosorbide dinitrate, the average plasma concentrations were higher and the area under the plasma concentration time curve was greater during sustained than during acute therapy (p less than 0.01). Reduction in standing systolic blood pressure was greater during acute than during sustained therapy (p less than 0.001). This reduction in systolic blood pressure was dose-related and persisted for 8 hours during acute therapy, but was not dose-related and was demonstrable for only 4 hours during sustained therapy. Compared with placebo therapy, exercise duration to the onset of angina and to the development of moderate angina increased significantly after each dose of isosorbide dinitrate for 8 hours during acute therapy but for only 2 hours during sustained therapy. During acute therapy, administration of a single dose of 15 or 30 mg of isosorbide dinitrate produced similar improvement in exercise tolerance as did a dose of 60 or 120 mg. During sustained therapy (15 mg four times daily), exercise tolerance increased to the same magnitude as with doses of 30, 60 or 120 mg four times daily. In most patients, near maximal improvement in exercise tolerance occurred after a dose of 15 or 30 mg four times daily. It is concluded that during sustained therapy with isosorbide dinitrate, partial tolerance to the antianginal and circulatory effects develops rapidly.

Trainsdermal nitroglycerin in angina pectoris

The hemodynamic and antianginal efficacy of transdermal nitroglycerin (TGTN) patches were assessed in patients with chronic, stable angina pectoris. In 11 patients, acute dosing with 10, 20 and 30 cm2 of TGTN (designed to deliver 5, 10 and 15 mg GTN over 24 hours) improved treadmill walking time 2 and 4 hours after application, but no clinical effects were seen at 24 hours. In a second study in 6 patients with doses of 30, 60 and 90 cm2 of TGTN treadmill walking time was improved at 2 and 4 hours, but no changes were seen at 24 hours except with the 90-cm2 preparation. After daily therapy with 30-cm2 patches of TGTN for 1 to 2 weeks, exercise tolerance was similar to that seen during daily placebo therapy. These results suggest that TGTN patches are of inadequate size to produce 24-hour antianginal protection. During sustained therapy, tolerance develops to the antianginal efficacy of this form of GTN administration.

Tolerance to the circulatory effects of oral isosorbide dinitrate: Rate of development and cross tolerance to glyceryl trinitrate

The effects of 15, 30, 60 and 120 mg of isosorbide dinitrate (ISDN) on systolic blood pressure (SBP) and heart rate (HR) were compared after acute oral administration and during sustained therapy four times daily with ISDN in six patients. After any given dose, plasma ISDN levels were higher during sustained therapy than during acute therapy. The average peak reduction in standing SBP occurred at 2 hours after 15, 30, 60 and 120 mg of ISDN; the values were 39, 42, 45 and 46 mm Hg, respectively, after acute therapy and 21, 20, 26 and 24 mm Hg, respectively, during sustained therapy (p < 0.01). Compared with placebo, the reduction in SBP was still apparent 6 hours after any given dose of ISDN during acute but not during sustained therapy (p < 0.01). HR increased significantly only after acute therapy.The rapidity of development of tolerance to ISDN and cross–tolerance to glyceryl trinitrate (GTN) was evaluated in eight other patients. The average peak reduction in SBP after the first dose of 15 mg of ISDN was 36 mm Hg, but after therapy with ISDN every 6 hours, the fifth dose of 15 mg of ISDN produced a peak reduction in SBP of only 7 mm Hg (p < 0.001). The first dose of 0.6 mg GTN before therapy with ISDN produced a peak reduction in SBP of 40 mm Hg, but after therapy with ISDN every 6 hours for 5 days, the same dose of GTN produced a maximum reduction in SBP of only 10 mm Hg (p < 0.001).The results show that partial circulatory tolerance to ISDN and cross–tolerance to GTN developed rapidly during regular therapy with ISDN. The plasma ISDN concentrations were higher during sustained than after acute therapy, suggesting that the tolerance (tachyphylaxis) to nitrates in man is due to the diminution of the end organ response and not to the accelerated metabolism of nitrates.

Tolerance to isosorbide dinitrate: rate of development and reversal.

The circulatory response and plasma concentrations of isosorbide dinitrate (ISDN) were determined in 10 patients with chronic, stable angina after administration of 5 mg of sublingual ISDN during the control stage, after 48 hr of therapy with 15 mg of ISDN orally every 6 hr, and subsequently after a 48 hr period when ISDN was substituted by placebo four times daily. Initially, sublingual ISDN induced major reductions in both supine and standing systolic and diastolic blood pressure, but after 45 hr of therapy with oral ISDN, there was a significantly diminished vasodepressor response in both positions. Subsequently, when placebo was substituted for ISDN, the circulatory response initially seen was restored within 21 hr. Plasma ISDN concentrations after the test sublingual dose were slightly higher after 48 hr of oral ISDN dosing (i.e., the tolerant state) than at the start of the study. This suggests that tolerance is unlikely to be caused by reduced bioavailability or accelerated elimination of ISDN. It is possible that tolerance is related to accumulation of ISDN metabolites. The attenuation of the circulatory response to ISDN may be related to the altered antianginal efficacy commonly seen during sustained therapy with ISDN.

Concurrent hydralazine administration prevents nitroglycerin-induced hemodynamic tolerance in experimental heart failure.

BackgroundOrganic nitrates such as nitroglycerin and isosorbide dinitrate are useful in the treatment of congestive heart failure (CHF), but tolerance develops rapidly during continuous administration. Because combination therapy of nitrate and hydralazine has been shown to provide both short- and long-term benefit but nitrate alone produces hemodynamic tolerance, we questioned whether hydralazine can preserve the favorable preload effects of nitroglycerin. Methods and ResultsUsing an in vivo model of nitroglycerin tolerance in the CHF rat, we examined the effects of hydralazine bolus dosing during continuous nitroglycerin infusion. Continuous infusion of nitroglycerin alone (10 jpg/mmn) produced initial reductions in left ventricular end-diastolic pressure of 40-50%, which returned to baseline by 8 hours (tolerance development). Coadministration of hydralazine (2X0.1 mg) maintained the effects of nitroglycerin infusion on left ventricular end-diastolic pressure (45% reduction at 10 hours). This hydralazine dose alone reduced left ventricular peak systolic pressure by approximately 12 ± 3% but had no effect on left ventricular end-diastolic pressure. Hydralazine dosing did not affect steady-state plasma concentrations of nitroglycerin or metabolites, and hydralazine was unable to prevent nitroglycerin tolerance induced in vitro. ConclusionsThe beneficial interaction of hydralazine on the preload effects of nitroglycerin may explain the long-term clinical efficacy of hydralazine/nitrate combination in CHF. Our results also suggest that the mechanism of in vivo nitrate tolerance in CHF may be systemic rather than vascular in origin. (Circulation 1991;84:35–39)

Oral isosorbide dinitrate in the treatment of angina pectoris. Dose-response relationship and duration of action during acute therapy.

The duration of effects of single oral doses of 15, 30 and 60 mg of isosorbide dinitrate (ISDN) were studied in 12 patients with stable, exercise-induced angina pectoris. The effects of a 120-mg dose also studied in seven of these 12 patients. The average peak values for plasma ISDN concentration were 14.3, 17.5 and 26.0 ng/ml after 15, 30, 60 and 120 mg of ISDN, respectively, and there was a 5-, 12-, 6-, and fold interindividual variation in peak plasma concentration at these doses. At rest, both the systolic diastolic blood pressures decreased after each dose of ISDN in both the supine (p < 0.05) and standing (p < 0.01) positions. The reduction in systolic blood pressure was more marked in the standing position. effect occurred at 1 hour and persisted for 6 hours after 15 mg of ISDN and for 8 hours after other doses ISDN. Exercise duration to the onset of angina and to the development of moderate angina increased similar degree after each dose of ISDN compared with placebo values (p < 0.001). This was apparent hour and the effects persisted for 8 hours. The maximum increase in walking time to angina occurred after mg in six patients, after 30 mg in two patients, and after 60 mg in three patients. One patient did not improve after any of the doses. The heart rate (p < 0.01) and rate-pressure product (p < 0.05) at the onset of angina after any dose of ISDN increased compared with placebo values. However, ST-segment depression at the onset of angina was similar after ISDN and placebo. At the onset of moderate angina, the values for rate-pressure product after ISDN were similar to those after placebo, but ST-segment depression was less after ISDN (p < 0.05).These data show that administration of single doses of ISDN from 15-120 mg increased exercise tolerance to angina for 8 hours, but for the whole group, higher doses did not have a quantitative greater effect on exercise tolerance than the lower doses.

Mechanisms of nitrate tolerance

SummaryThere is now little dispute that clinical tolerance of organic nitrates occurs, particularly when these drugs are used by themselves to treat patients with stable angina pectoris and congestive heart failure. Classical hypotheses of nitrate tolerance suggest the phenomenon to result from vascular depletion of critical sulfhydryl groups, which are necessary to bring about vasorelaxation from nitrates. While this mechanism of nitrate tolerance probably operates when isolated blood vessels are exposed to high concentrations of nitrate in vitro, there is little evidence to suggest that it contributes to clinical nitrate tolerance. Instead, emerging data suggest that nitrates can cause significant shifts in fluid distribution and secretion of neurohormonal factors that can modulate their vasorelaxant effects. use of angiotensin converting enzyme inhibitors and diuretics in conjunction with nitrates may alleviate the development of tolerance, but the experience has not been universally favorable. Other receptor-effector systems that affect cardiovascular function, such as the adrenergic system, may also be affected by nitrate tolerance. The mechanisms of nitrate tolerance are therefore likely to be multifactorial, involving vascular biochemical changes, physiologic compensation, and possibly receptor regulation.

Clinical pharmacology of organic nitrates.

Although organic nitrates have been used in cardiovascular therapy for many years, various aspects of their pharmacology remain poorly understood. It is now known that organic nitrates produce nitric oxide (NO) in vascular smooth muscle cells, catalyzed by a membrane-bound enzyme that is not glutathione-S-transferase. Other nitrovasodilators, such as organic nitrites, sodium nitroprusside, and S-nitrosothiols, do not utilize the same enzyme for NO generation. The short-term hemodynamic action of various organic nitrates has been shown to be related to their pharmacokinetics, but their long-term therapeutic effects are limited by the development of pharmacologic tolerance. Nitrate sensitivity in patients can be restored daily after a nitrate-free period of 8-12 hours. Coadministration of nitrates with other vasodilators, such as captopril and hydralazine, may avoid the development of nitrate tolerance in patients with congestive heart failure.

Calcitonin gene-related peptide-dependent vascular relaxation of rat aorta. An additional mechanism for nitroglycerin.

We investigated the involvement of calcitonin gene-related peptide (CGRP) in the vasodilatory mechanism of action of nitric oxide (NO) donors. The functional role of CGRP in NO donor-induced vasodilation of isolated rat aortic rings was determined by incubating these drugs with and without CGRP(8-37), a selective CGRP receptor antagonist. CGRP(8-37) (0.63 microM) induced rightward shifts in the vasodilatory concentration-response curves for nitroglycerin (NTG), Pilotys acid (PA), and SIN-1 (linsidomine). The EC(50) values for NTG, PA, and SIN-1 were increased by 8.3-, 5.2-, and 2.3-fold, respectively (P < 0.05). The release of CGRP from rat aorta in response to NTG and PA was measured specifically by radioimmunoassay. Thirty-minute incubations of NTG or PA with rat aorta induced 189.5 and 214.6% increases, respectively, in CGRP release when compared with the control (P < 0.05). The concentration-response curves of sodium nitroprusside (SNP), S-nitroso-acetylpenicillamine (SNAP), tetranitromethane (TNM), diethylamine NO complex (DEA-NO), and diethylenetriamine/nitric oxide adduct (DETA NONOate) were not inhibited significantly by CGRP(8-37) co-incubation (P 0.05). NO donors also were incubated with aortic strips, and NTG and PA alone induced significant formation of hydroxylamine, a NO(-) metabolite (232.4 and 364.9%, respectively, P < 0.05). These results indicate that only NTG and PA, and to a lesser extent SIN-1, stimulate the release of CGRP from the rat aorta, which subsequently contributes to the vasodilatory activity of these agents. The hydroxylamine formation suggests a possible link between NO(-) generation and CGRP release from the vascular wall.

Tolerance to relaxation in rat aorta: comparison of an S-nitrpsothiol with nitroglycerin

Tolerance and cross-tolerance to the relaxant effects of S-nitroso-N-acetylpenicillamine (SNAP) and nitroglycerin were examined in rat aortic rings. Nitroglycerin-tolerant rings remained fully responsive to SNAP and sodium nitroprusside. Thus, reduced metabolic activation of nitroglycerin, rather than impaired guanylate cyclase activity, appeared to be the operating mechanism for nitrate tolerance in this preparation. Under similar conditions, SNAP incubation induced less tolerance than nitroglycerin. S-nitrosothiols, therefore, appear to be less tolerance-producing than nitroglycerin.