rted doses have been calculated by simply multiplying the flow rate of the solution by the solution's original concentration of nitroglycerin. the actual doses delivered have been less, sometimes much less, than those reported. some in-line intravenous filters also absorb nitroglycerin; these filters should be avoided. because of the problem of nitroglycerin absorption by polyvinyl chloride (pvc) tubing, nitroglycerin injection should be used with the least absorptive infusion tubing (i.e., non-pvc tubing) available. dosing instructions must be followed with care. when the appropriate infusion sets are used, the calculated dose will be delivered to the patient, because the loss of nitroglycerin injection seen with standard pvc tubing will be avoided. the dosages reported in published studies utilized general-use pvc administration sets, and recommended doses based on this experience will be too high when the low-absorbing infusion sets are used.

ontinuous hours of every 24- hour day. during the nitrate-free intervals in some of these trials, anginal attacks have been more easily provoked than before treatment, and patients have demonstrated hemodynamic rebound and decreased exercise tolerance. the importance of these observations to the routine, clinical use of intravenous nitroglycerin is not known. lower concentrations of nitroglycerin increase the potential precision of dosing, but these concentrations increase the total fluid volume that must be delivered to the patient. total fluid load may be a dominant consideration in patients with compromised function of the heart, liver, and/or kidneys. nitroglycerin infusions should be administered only via a pump that can maintain a constant infusion rate. intracoronary injection of nitroglycerin infusions has not been studied.

ld not exceed 400 mcg/ml. see chart. note: if the concentration is adjusted, it is imperative to flush or replace the infusion set before a new concentration is utilized. if the set were not flushed or replaced, it could take minutes to hours, depending upon the flow rate and the dead space of the set, for the new concentration to reach the patient. invert the glass parenteral bottle several times to assure uniform dilution of the nitroglycerin. dosage is affected by the type of container and administration set used. see warnings . although the usual starting adult dose range reported in clinical studies was 25 mcg/min or more, these studies used pvc administration sets. the use of non-absorbing tubing will result in the need for reduced doses. if a peristaltic action infusion pump is used, an appropriate administration set should be selected with a drip chamber that delivers approximately 60 microdrops/ml. table 1 and the nitroglycerin injection dilution table below may be used to calculate the nitroglycerin dilution and flow rate in microdrops/minute to achieve the desired nitroglycerin injection administration rate. if a volumetric infusion pump is used, an appropriate volumetric infusion pump connector set should be selected. table 1 below may still be used; however, flow rate will be determined directly by the infusion pump, independent of the drop size of the appropriate set drip chambers. thus, the reference to ``microdrops/min′′ is not applicable, and the corresponding flow rate in ml/hr should be used to determine pump settings. when using a non-absorbing infusion set, the initial dosage should be 5 mcg/min delivered through an infusion pump capable of exact and constant delivery of the drug. subsequent titration must be adjusted to the clinical situation, with dose increments becoming more cautious as partial response is seen. initial titration should be in 5 mcg/min increments, with increases every 3-5 minutes until some response is noted. if no response is seen at 20 mcg/min, increments of 10 and later 20 mcg/min can be used. once a partial blood pressure response is observed, the dose increase should be reduced and the interval between increases should be lengthened. some patients with normal or low left ventricular filling pressures or pulmonary capillary wedge pressure (e.g., angina patients without other complications) may be hypersensitive to the effects of nitroglycerin and may respond fully to doses as small as 5 mcg/min. these patients require especially careful titration and monitoring. there is no fixed optimum dose of nitroglycerin. due to variations in the responsiveness of individual patients to the drug, each patient must be titrated to the desired level of hemodynamic function. therefore, continuous monitoring of physiologic parameters (i.e., blood pressure and heart rate in all patients, other measurements such as pulmonary capillary wedge pressure, as appropriate) must be performed to achieve the correct dose. adequate systemic blood pressure and coronary perfusion pressure must be maintained. dilution: nitroglycerin injection is supplied in 5 mg/ml solution. a dilution and administration scheme for nitroglycerin injection is shown in table 1 below. table 1 60 microdrops = 1 ml solution concentration (mcg/ml) 100 200 400 dose (mcg/min) flow rate (microdrops/min = ml/hr) 5 3 — — 10 6 3 — 15 9 — — 20 12 6 3 30 18 9 — 40 24 12 6 60 36 18 9 80 48 24 12 120 72 36 18 160 96 48 24 240 — 72 36 320 — 96 48 480 — — 72 640 — — 96 nitroglycerin injection dilution table (diluent: dextrose 5% injection or sodium chloride injection (0.9%)) each ml of nitroglycerin injection contains 5 mg of nitroglycerin. total contents: each 10 ml vial contains 50 mg of nitroglycerin. ml of nitroglycerin injection mg final concentration 100 mcg/ml 200 mcg/ml 400 mcg/ml volume q.s. to q.s. to q.s. to 5 ml 25 mg 250 ml 125 ml - - - 10 ml 50 mg 500 ml 250 ml 125 ml 20 ml 100 mg 1000 ml 500 ml 250 ml 40 ml 200 mg - - - 1000 ml 500 ml note: parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

s the anti-anginal efficacy of continuously-delivered nitrates. in the large majority of these trials, active agents were indistinguishable from placebo after 24 hours (or less) of continuous therapy. attempts to overcome nitrate tolerance by dose escalation, even to doses far in excess of those used acutely, have consistently failed. only after nitrates have been absent from the body for several hours has their anti-anginal efficacy been restored. pharmacokinetics: the volume of distribution of nitroglycerin is about 3 l/kg, and nitroglycerin is cleared from this volume at extremely rapid rates, with a resulting serum half-life of about 3 minutes. the observed clearance rates (close to 1 l/kg/min) greatly exceed hepatic blood flow; known sites of extrahepatic metabolism include red blood cells and vascular walls. the first products in the metabolism of nitroglycerin are inorganic nitrate and the 1,2- and 1,3- dinitroglycerols. the dinitrates are less effective vasodilators than nitroglycerin, but they are longer-lived in the serum, and their net contribution to the overall effect of chronic nitroglycerin regimens is not known. the dinitrates are further metabolized to (non-vasoactive) mononitrates and, ultimately, to glycerol and carbon dioxide. to avoid development of tolerance to nitroglycerin, drug-free intervals of 10-12 hours are known to be sufficient; shorter intervals have not been well studied. in one well-controlled clinical trial, subjects receiving nitroglycerin appeared to exhibit a rebound or withdrawal effect, so that their exercise tolerance at the end of the daily drug-free interval was less than that exhibited by the parallel group receiving placebo. clinical trials: blinded, placebo-controlled trials of intravenous nitroglycerin have not been reported, but multiple investigators have reported open-label studies, and there are scattered reports of studies in which intravenous nitroglycerin was tested in blinded fashion against sodium nitroprusside. in each of these studies, therapeutic doses of intravenous nitroglycerin were found to reduce systolic and diastolic arterial blood pressure. the heart rate was usually increased, presumably as a reflexive response to the fall in blood pressure. coronary perfusion pressure was usually, but not always, maintained. intravenous nitroglycerin reduced central venous pressure (cvp), right atrial pressure (rap), pulmonary arterial pressure (pap), pulmonary-capillary wedge pressure (pcwp), pulmonary vascular resistance (pvr), and systemic vascular resistance (svr). when these parameters were elevated, reducing them toward normal usually caused a rise in cardiac output. conversely, intravenous nitroglycerin usually reduced cardiac output when it was given to patients whose cvp, rap, pap, pcwp, pvr, and svr were all normal. most clinical trials of intravenous nitroglycerin have been brief; they have typically followed hemodynamic parameters during a single surgical procedure. in one careful study, one of the few that lasted more than a few hours, continuous intravenous nitroglycerin had lost almost all of its hemodynamic effect after 48 hours. in the same study, patients who received nitroglycerin infusions for only 12 hours out of each 24 demonstrated no similar attenuation of effect. these results are consistent with those seen in multiple large, double-blind, placebo-controlled trials of other formulations of nitroglycerin and other nitrates.

inical trial, subjects receiving nitroglycerin appeared to exhibit a rebound or withdrawal effect, so that their exercise tolerance at the end of the daily drug-free interval was less than that exhibited by the parallel group receiving placebo.

/kg/day for six months prior to mating of the f 0 generation with treatment continuing through successive f 1 and f 2 generations. the high-dose was associated with decreased feed intake and body weight gain in both sexes at all matings. no specific effect on the fertility of the f 0 generation was seen. infertility noted in subsequent generations, however, was attributed to increased interstitial cell tissue and aspermatogenesis in the high dose males. in this three-generation study there was no clear evidence of teratogenicity.

troglycerin usually reduced cardiac output when it was given to patients whose cvp, rap, pap, pcwp, pvr, and svr were all normal. most clinical trials of intravenous nitroglycerin have been brief; they have typically followed hemodynamic parameters during a single surgical procedure. in one careful study, one of the few that lasted more than a few hours, continuous intravenous nitroglycerin had lost almost all of its hemodynamic effect after 48 hours. in the same study, patients who received nitroglycerin infusions for only 12 hours out of each 24 demonstrated no similar attenuation of effect. these results are consistent with those seen in multiple large, double-blind, placebo-controlled trials of other formulations of nitroglycerin and other nitrates.