NITROGLYCERIN

Nitroglycerin is a peculiar chemical because it is both an explosive powder and an effective antianginal agent. It is an organic nitrate (glyceryl trinitrate) that relaxes vascular smooth muscle and produces a generalized vasodilation.

NITRIC OXIDE

Nitroglycerin binds to the surface of endothelial cells and undergoes two chemical reductions to form nitric oxide (NO). The nitric oxide then moves out of the endothelial cell and into an adjacent smooth muscle cell, where it promotes the formation of cyclic guanosine monophosphate (cGMP), which then promotes muscle relaxation. Vasodilation is a prominent action of nitric oxide, which was known as endothelium-derived relaxing factor before its chemical identification.

ACTIONS

Nitroglycerin has a dose-dependent vasodilator effect in arteries and veins and is active in the systemic and pulmonary circulations. When the drug is given by continuous infusion, venous dilator effects are prominent at low dose rates (< 40 ug/min) and arterial dilator effects predominate at high dose rates (> 200 ug/min). As low-dose infusions are titrated upward, the earliest response is a decrease in cardiac filling pressures (i.e., central venous pressure and wedge pressure) with little or no change in cardiac output. As the dose rate is increased further, the cardiac output begins to rise as a result of progressive arterial vasodilation. Further increases in the dose rate will eventually produce a drop in blood pressure. The hemodynamic responses to intravenous nitroglycerin have a rapid onset and short duration, which permits rapid dose titration.

Antiplatelet Effects

Nitrates can inhibit platelet aggregation via the mechanism proposed for the vasodilator actions. Because platelet thrombi are believed to play an important role in the pathogenesis of acute myocardial infarction, the antiplatelet actions of nitroglycerin have been proposed as the mechanism for the antianginal effects of the drug. This may explain why the antianginal efficacy of nitroglycerin is not shared by other vasodilator agents.

Indications

Intravenous nitroglycerin can be used to decrease left-ventricular filling pressures (low dose), augment cardiac output (intermediate dose), or lower blood pressure (high dose). It is also useful in relieving anginal chest pain.

DRUG ADMINISTRATION

A nitroglycerin dose chart is shown in Table 18.6. The infusion rates in this chart are based on a drug concentration of 400 ug/mL in the infusion solution.

Sorption

Nitroglycerin binds to soft plastics such as polyvinylchloride (PVC), which is a common constituent in plastic bags and infusion tubing. As much as 80% of the drug can be lost by sorption. Glass and hard plastics do not adsorb nitroglycerin, so the problem of adsorption can be eliminated by using glass bottles and stiff polyethylene tubing. Drug manufacturers often provide specialized infusion sets to deliver nitroglycerin. (For a comprehensive description of nitroglycerin adsorption, see the Handbook on Injectable Drugs, pp 777-781.)

Nitroglycerin infusions should begin at a rate of 5 ug/min. The dose rate is then increased in 5-ug/min increments every 5 minutes until the desired effect is achieved. Although effective dose rates vary, the dose requirement should not exceed 400 ug/min in most patients. High dose requirements (e.g., > 350 ug/min) are often the result of drug loss via adsorption, or nitrate tolerance (see below).

ADVERSE EFFECTS

Nitroglycerin can produce three types of adverse reactions. One is flow related, another is related to oxidant stress, and the final one is related to the way the drug is administered.

Flow-Related Effects

Excessive flow in the cerebral and pulmonary circulations can create complications. Nitroglycerin seems adept at increasing cerebral blood flow (headache is a common complaint), and this can increase intracranial pressure and produce symptomatic intracranial hypertension . Because of this effect, nitroglycerin is avoided in patients with increased intracranial pressure. Increases in pulmonary blood flow can become a problem when the augmented flow occurs in areas of the lung that are poorly ventilated. This increases shunt fraction and can lead to hypoxemia. This effect can be prominent in the acute respiratory distress syndrome , where much of the lung is poorly ventilated.

Methemoglobinemia

Nitroglycerin metabolism produces inorganic nitrites, and accumulation of nitrites can result in the oxidation of heme-bound iron in hemoglobin, as shown below.

Hb – Fe(II) + NO2 + H+ —»  Hb – Fe(III) + HONO

(18.1)

The oxidation of iron from the Fe(II) to Fe(III) state creates methemoglobin (metHb). Oxidized iron does not carry oxygen effectively, and thus metHb accumulation can impair tissue oxygenation. Clinically significant methemoglobinemia is not a common complication of nitroglycerin therapy and usually occurs only at very high dose rates . MetHb accumulation has few specific manifestations other than the characteristic brown discoloration of blood (due to the brown color of metHb). MetHb can be detected by light reflection (oximetry). Pulse oximeters do not reliably detect metHb (30), and the measurement should be performed by more sophisticated oximeters (called co-oximeters) in the clinical laboratory.

MetHb levels above 3% (fraction of total hemoglobin) are abnormal. Levels above 40% can produce tissue ischemia, and levels above 70% are lethal . If there is no evidence of tissue hypoxia, discontinuing nitroglycerin is all that is required. If tissue oxygenation is impaired (e.g., lactic acidosis), metHb can be chemically converted back to normal hemoglobin with methylene blue (a reducing agent), 2 mg/kg IV over 10 minutes.

Solvent Toxicity

Nitroglycerin does not readily dissolve in aqueous solutions, and nonpolar solvents such as ethanol and propylene glycol are required to keep the drug in solution. These solvents can accumulate during continuous infusion.

Ethanol intoxication has been reported in association with nitroglycerin infusions. Manifestations include a change in mental status and garbled speech. Hypotension can also occur. A blood ethanol level will confirm the diagnosis. Propylene glycol toxicity has also been reported, and because some commercial nitroglycerin preparations contain 30 to 50% propylene glycol , clinical toxicity may be more common than suspected. Toxic manifestations include altered mental status that can progress to coma, metabolic acidosis, and hemolysis. The propylene glycol level in blood confirms the diagnosis.

In patients who develop a change in mental status during prolonged or high-dose nitroglycerin infusions, the serum osmolal gap (i.e., the difference between measured and calculated serum osmolality) might be a valuable screening test for possible solvent toxicity. The osmolal gap should be elevated (> 10 mOsm/kg) by the presence of either solvent in the bloodstream. An elevated gap would then prompt more specific assays to identify the toxin.

NITRATE TOLERANCE

Tolerance to the vasodilator and antiplatelet actions of nitroglycerin is more common than suspected and can appear after only 24 hours of continuous drug administration. No single mechanism seems to explain this phenomenon. One possible cause is the depletion of reducing agents in the vascular endothelium, which impairs the conversion of nitroglycerin to nitric oxide. This mechanism is supported by the association of nitrate tolerance with decreased nitric oxide production. However, the administration of reducing agents (e.g., N-acetylcysteine) does not consistently restore responsiveness in nitrate tolerance. At present, the most effective method for restoring nitroglycerin responsiveness is to discontinue drug administration for at least 6 to 8 hours each day.

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