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 (nonvasoactive) 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.

In healthy volunteers, steady-state plasma concentrations of nitroglycerin are reached by about 2 hours after application of a patch and are maintained for the duration of wearing the system (observations have been limited to 24 hours). Upon removal of the patch, the plasma concentration declines with a half-life of about an hour.

Clinical Trials

Regimens in which nitroglycerin patches were worn for 12 hours daily have been studied in well controlled trials up to 4 weeks in duration. Starting about 2 hours after application and continuing until 10-12 hours after application, patches that deliver at least 0.4 mg of nitroglycerin per hour have consistently demonstrated greater antianginal activity than placebo.

Lower-dose patches have not been as well studied, but in one large, well-controlled trial in which higher-dose patches were also studied, patches delivering 0.2 mg/hr had significantly less antianginal activity than placebo.

It is reasonable to believe that the rate of nitroglycerin absorption from patches may vary with the site of application, but this relationship has not been adequately studied.

The onset of action of transdermal nitroglycerin is not sufficiently rapid for this product to be useful in aborting an acute anginal episode.

General

Severe hypotension, particularly with upright posture, may occur with even small doses of nitroglycerin, particularly in the elderly. This drug should therefore be used with caution in elderly patients who may be volume depleted, are on multiple medications,  or who, for whatever reason, are already hypotensive. Hypotension induced by nitroglycerin may be accompanied by paradoxical bradycardia and increased angina pectoris. Elderly patients may be more susceptible to hypotension and may be at greater risk of falling at the therapeutic doses of nitroglycerin. Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy, particularly in the elderly.

As tolerance to other forms of nitroglycerin develops, the effect of sublingual nitroglycerin on exercise tolerance, although still observable, is somewhat blunted.

In industrial workers who have had long-term exposure to unknown (presumably high) doses of organic nitrates, tolerance clearly occurs. Chest pain, acute myocardial infarction, and even sudden death have occurred during temporary withdrawal of nitrates from these workers, demonstrating the existence of true physical dependence.

Several clinical trials in patients with angina pectoris have evaluated nitroglycerin regimens which incorporated a 10-12 hour nitrate-free interval. In some of these trials, an increase in the frequency of anginal attacks during the nitrate-free interval was observed in a small number of patients. In one trial, patients demonstrated decreased exercise tolerance at the end of the nitrate-free interval. Hemodynamic rebound has been observed only rarely; on the other hand, few studies were so designed that rebound, if it had occurred, would have been detected. The importance of these observations to the routine, clinical use of transdermal nitroglycerin is unknown.

Information for Patients

Daily headaches sometimes accompany treatment with nitroglycerin. In patients who get these headaches, the headaches may be a marker of the activity of the drug. Patients should resist the temptation to avoid headaches by altering the schedule of their treatment with nitroglycerin, since loss of headache may be associated with simultaneous loss of antianginal efficacy.

Treatment with nitroglycerin may be associated with lightheadedness on standing, especially just after rising from a recumbent or seated position. This effect may be more frequent in patients who have also consumed alcohol.

After normal use, there is enough residual nitroglycerin in discarded patches that they are a potential hazard to children and pets.

A patient information leaflet is supplied with the systems.

Drug Interactions

The vasodilating effects of nitroglycerin may be additive with those of other vasodilators. Alcohol, in particular, has been found to exhibit additive effects of this variety.

Concomitant use of Nitroglycerin Transdermal Systems with phosphodiesterase inhibitors in any form is contraindicated (see CONTRAINDICATIONS).

Concomitant use of Nitroglycerin Transdermal Systems with riociguat, a soluble guanylate cyclase stimulator, is contraindicated (see CONTRAINDICATIONS).

Marked symptomatic orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used in combination. Dose adjustments of either class of agents may be necessary.

Carcinogenesis , Mutagenesis , Impairment of Fertility

Animal carcinogenesis studies with topically applied nitroglycerin have not been performed.

Rats receiving up to 434 mg/kg/day of dietary nitroglycerin for 2 years developed dose-related fibrotic and neoplastic changes in liver, including carcinomas, and interstitial cell tumors in testes. At high dose, the incidences of hepatocellular carcinomas in both sexes were 52% vs. 0% in controls, and incidences of testicular tumors were 52% vs. 8% in controls. Lifetime dietary administration of up to 1058 mg/kg/day of nitroglycerin was not tumorigenic in mice.

Nitroglycerin was weakly mutagenic in Ames tests performed in two different laboratories. Nevertheless, there was no evidence of mutagenicity in an in vivo dominant lethal assay with male rats treated with doses up to about 363 mg/kg/day, p.o., or in in vitro cytogenetic tests in rat and dog tissues.

In a three-generation reproduction study, rats received dietary nitroglycerin at doses up to about 434 mg/kg/day for 6 months prior to mating of the F0 generation with treatment continuing through successive F1 and F2 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 F0 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.

Pregnancy Category C

Animal teratology studies have not been conducted with Nitroglycerin Transdermal Systems. Teratology studies in rats and rabbits, however, were conducted with topically applied nitroglycerin ointment at doses up to 80 mg/kg/day and 240 mg/kg/day, respectively. No toxic effects on dams or fetuses were seen at any dose tested. There are no adequate and well-controlled studies in pregnant women. Nitroglycerin should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether nitroglycerin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when nitroglycerin is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of transdermal nitroglycerin did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.

Additional clinical data from the published literature indicate that the elderly demonstrate increased sensitivity to nitrates, which may result in hypotension and increased risk of falling. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hemodynamic Effects

The ill effects of nitroglycerin overdose are generally the result of nitroglycerin's capacity to induce vasodilatation, venous pooling, reduced cardiac output, and hypotension. These hemodynamic changes may have protean manifestations, including increased intracranial pressure, with any or all of persistent throbbing headache, confusion, and moderate fever; vertigo; palpitations; visual disturbances; nausea and vomiting (possibly with colic and even bloody diarrhea); syncope (especially in the upright posture); air hunger and dyspnea, later followed by reduced ventilatory effort; diaphoresis, with the skin either flushed or cold and clammy; heart block and bradycardia; paralysis; coma; seizures; and death.

Laboratory determinations of serum levels of nitroglycerin and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of nitroglycerin overdose.

No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of nitroglycerin and its active metabolites. Similarly, it is not known which, if any, of these substances can usefully be removed from the body by hemodialysis.

No specific antagonist to the vasodilator effects of nitroglycerin is known, and no intervention has been subject to controlled study as a therapy of nitroglycerin overdose. Because the hypotension associated with nitroglycerin overdose is the result of venodilatation and arterial hypovolemia, prudent therapy in this situation should be directed toward an increase in central fluid volume. Passive elevation of the patient's legs may be sufficient, but intravenous infusion of normal saline or similar fluid may also be necessary.

The use of epinephrine or other arterial vasoconstrictors in this setting is likely to do more harm than good.

In patients with renal disease or congestive heart failure, therapy resulting in central volume expansion is not without hazard. Treatment of nitroglycerin overdose in these patients may be subtle and difficult, and invasive monitoring may be required.

Methemoglobinemia

Nitrate ions liberated during metabolism of nitroglycerin can oxidize hemoglobin into methemoglobin. Even in patients totally without cytochrome b5 reductase activity, however, and even assuming that the nitrate moieties of nitroglycerin are quantitatively applied to oxidation of hemoglobin, about 1 mg/kg of nitroglycerin should be required before any of these patients manifests clinically significant (≥10%) methemoglobinemia. In patients with normal reductase function, significant production of methemoglobin should require even larger doses of nitroglycerin. In one study in which 36 patients received 2-4 weeks of continuous nitroglycerin therapy at 3.1 to 4.4 mg/hr, the average methemoglobin level measured was 0.2%; this was comparable to that observed in parallel patients who received placebo.

Notwithstanding these observations, there are case reports of significant methemoglobinemia in association with moderate overdoses of organic nitrates. None of the affected patients had been thought to be unusually susceptible.

Methemoglobin levels are available from most clinical laboratories. The diagnosis should be suspected in patients who exhibit signs of impaired oxygen delivery despite adequate cardiac output and adequate arterial pO2. Classically, methemoglobinemic blood is described as chocolate brown, without color change on exposure to air.

When methemoglobinemia is diagnosed, the treatment of choice is methylene blue, 1-2 mg/kg intravenously.