What is the most common adverse effect associated with administration of nitroglycerin?

Nitroglycerin

Nitro-Bid, Nitrostat, Nitro-Time, Nitro-Dur, Nitrolingual, Nitromist, Minitran, Rectiv, and generics

Vasodilator, antihypertensive

Injection: 5 mg/mL (10 mL); contains alcohol or propylene glycol

Prediluted injection in D5W: 100 mCg/mL (250 mL), 200 mCg/mL (250 mL), 400 mCg/mL (250 mL); contains alcohol and propylene glycol

Sublingual tabs (Nitrostat and generics): 0.3, 0.4, 0.6 mg

Sustained-release caps (Nitro-Time and generics): 2.5, 6.5, 9 mg

Ointment, topical (Nitro-Bid): 2% (1, 30, 60 g)

Ointment, rectal (Rectiv): 0.4% (30 g); contains propylene glycol

Patch (Nitro-Dur, Minitran, and generics): 2.5 mg/24 hr (0.1 mg/hr), 5 mg/24 hr (0.2 mg/hr), 7.5 mg/24 hr (0.3 mg/hr), 10 mg/24 hr (0.4 mg/hr), 15 mg/24 hr (0.6 mg/hr), 20 mg/24 hr (0.8 mg/hr) (30s, 100s)

Spray, translingual (Nitrolingual and generics): 0.4 mg per metered spray (4.9, 12 g; delivers 60 and 200 doses, respectively); contains 20% alcohol (flammable)

Aerosol spray, translingual (Nitromist): 0.4 g per spray (4.1, 8.5 g; delivers 90 and 230 doses, respectively); contains peppermint oil and menthol

Abstract

Nitroglycerin also known as glyceryl trinitrate is used as an anti-angina vasodilating agent. It is a slightly volatile odorless oily liquid with sweet, aromatic, and pungent taste. Nitroglycerin is soluble in water, ethanol, and methanol and miscible with ether, acetone, and chloroform. The medical use of nitroglycerin is for treatment of human angina and left ventricular failure as a drug. Nitroglycerin may release to the environment through various waste streams. Occupational exposure to nitroglycerin may occur through dermal contact rather than inhalation with this compound at workplaces where nitroglycerin is produced or used. Toxic effects of nitroglycerin are caused by vasodilatation and methemoglobinemia.

Nitroglycerin

Nitrates decrease myocardial preload and, to a lesser extent, afterload. Nitrates increase venous capacitance and induce venous pooling, which decreases preload and myocardial oxygen demand. Direct vasodilation of coronary arteries may increase collateral blood flow to the ischemic myocardium.

Nitroglycerin has been used for decades in patients with suspected or known ACS. Most studies of IV NTG in the setting of ACS, however, are from the prefibrinolytic era. Although the data from multiple trials originally noted a 35% mortality reduction with IV NTG in the setting of AMI, this study preceded the modern era of aggressive reperfusion therapies coupled with potent anticoagulant and antiplatelet agents. No contemporary evidence (ie, in the reperfusion era of acute cardiac care) has shown improved outcomes with the routine use of any form of nitrate therapy in patients with AMI. In the ACS patient, it must be noted that the use of NTG in any formulation is another management option, yet its use is not mandatory. In situations in which hypotension is present or is anticipated to occur, it is very appropriate to withhold NTG in all formulations.

Patients with possible ACS and a systolic blood pressure greater than 90 mm Hg can receive a sublingual NTG tablet (0.4 mg [400 µg]) on presentation. If symptoms and pain are not fully relieved with three sublingual tablets, IV NTG can be considered. With bradycardia, hypotension, inferior wall STEMI, and right ventricular infarction, a sudden decrease in preload associated with NTG can result in profound hypotension. An initial infusion rate of 10 µg/min is titrated to pain symptoms. The emergency clinician can increase the infusion at regular intervals, allowing a 10% reduction in the mean arterial pressure if the patient is normotensive and a 20% to 30% reduction if hypertensive.

Nitroglycerin

Nitroglycerin (seeTable 62-14), which is a venodilator at low doses and an arteriolar dilator at higher doses, may prevent recurrent ischemia in patients with unstable angina, but no studies of sufficient statistical power have determined whether it reduces the risk of MI in this population of patients. In patients who complain of recurrent symptoms, nitroglycerin should be given sublingually or by buccal spray (0.3 to 0.6 mg). Patients with ongoing or recurrent chest pain should receive intravenous nitroglycerin (5 to 10 µg/minute with use of nonabsorbable tubing), with escalation of the dose in increments of 10 µg/minuteuntil symptoms resolve or adverse effects develop. Nitroglycerin’s most common adverse effects are headache, nausea, dizziness, hypotension, and reflex tachycardia.

Nitrate tolerance can be avoided by periodically providing the patient with a nitrate-free period (i.e., a brief cessation of drug administration). Nitroglycerin should not be given to patients who have received a phosphodiesterase-5 inhibitor (i.e., sildenafil, tadalafil, or vardenafil) within the previous 24 to 48 hours because severe hypotension may ensue.

6.2 Nitroglycerin

Nitroglycerin (melting point 14°C) is a liquid at room temperature. Nitroglycerin is lipophilic and a volatile compound. It is an ester that undergoes specific base catalyzed hydrolysis in aqueous solutions, but is relatively stable under acidic conditions. However, the drug is poorly soluble in water (solubility is about 1 mg/ml). Decreased potency of nitroglycerin sublingual tablets is mainly due to evaporation of nitroglycerin from the tablets (Fig. 6.2).

In conventional tablets (i.e., tablets without stabilizers), nitroglycerin evaporates from one tablet and enters into another, leading to uneven drug distribution from one tablet to another (Fig. 6.2). Furthermore, nitroglycerin migrates relatively easily from tablets to various materials such as paper, plastic, and cotton. The addition of excipients (i.e. stabilizers) to the tablets that lower the vapor pressure of nitroglycerin, such as the addition of 0.5 to 2% polyvinylpyrrolidone (polyvidone), has been shown to decrease nitroglycerin evaporation and migration [8]. Nitroglycerin sublingual tablets that are currently on the market contain stabilizers that enhance their physical stability.

3.5 Nitroglycerin-Mediated Dilation

Nitroglycerin-mediated dilation (NMD) is used to quantify the endothelium-independent maximal vascular dilatation following exogenous NTG supplementation and helps determine if impairments in vasodilatation are due to a loss in smooth-muscle cell integrity, or the inability of endothelial cells to release NO [93]. Nitroglycerin-mediated dilation is measured following at least 10 min of complete rest and is commonly performed after completion of the FMD assessment. The technical measurement settings remain similar to those used for FMD quantification, however, in NMD, the sphygmomanometer cuff inflation and deflation is replaced by a single high-dose (0.4 mg) intake of sublingual NTG spray or tablet. The peak vasodilatation is usually achieved 3–4 min following administration of NTG [93]. Similar to FMD, NMD is expressed as a percentage increase in dilation relative to the baseline diameter, and this ratio should be allometrically scaled in accordance with recent statistical guidelines [78,79]. Nitroglycerin-mediated dilation is less affected by diseases compared to FMD, although it has been suggested that reactive-oxygen species (important features of various cardiovascular diseases and atherosclerosis) might cause NO inactivation and thereby affect NMD values [75].

Nitroglycerin

Nitroglycerin (NTG) in either sublingual (SL) or spray form should be used for relief of angina and ischemia (ACC/AHA Class I indication; see reference for details on ACC/AHA indication classification). NTG 0.4 mg SL or spray may be given every 5 minutes for a total of three doses. If pain persists, NTG 10 μg/min continuous intravenous infusion should be started. The rate may be increased by 10 μg/min every 5 minutes until a maximum rate of 200 μg/min is reached.

NTG is contraindicated in patients who have taken a phosphodiesterase inhibitor for erectile dysfunction within 24 hours. Patients also should not take a phosphodiesterase inhibitor within 24 hours of NTG use. NTG should be used cautiously in patients at risk for severe hypotension, including those with aortic stenosis or right ventricular infarction. NTG should be tapered off slowly because abrupt discontinuation may cause rebound ischemia. Major side effects of NTG include headaches, hypotension, and methemoglobinemia (rare).

NTG is a peripheral and coronary vasodilator. NTG reduces preload via venous dilation, and achieves modest afterload reduction via arterial dilation. These effects result in decreased myocardial oxygen demand. In addition, NTG induces coronary vasodilation, thereby increasing oxygen delivery.

An overview of small, uncontrolled studies has suggested a mortality benefit; however, both the Fourth International Study of Infarct Survival (ISIS‐4) and Gruppo Italiano Sperimentazione Streptochinasi Infarto Miocardico ‐ 3 (GISSI‐3) studies have failed to confirm these findings.

Nitroglycerin.

Nitroglycerin is a very short-acting organic nitrate that is available in several formulations. As a sublingual spray or tablet, nitroglycerin is used in treating acute angina. As a transdermal patch or topical ointment, nitroglycerin is used in the prevention of angina and the treatment of congestive cardiac failure. In the ICU, nitroglycerin is typically administered as a continuous intravenous infusion for the:

Prevention of spasm in coronary artery bypass conduits.

Treatment of decompensated heart failure.

Treatment of acute myocardial ischemia.

Treatment of systemic and pulmonary hypertension.

The dose range is 0.25 to 5 μg/kg/min, and the clinical effect dissipates within a few minutes after the infusion is stopped. At lower doses (<2 μg/kg/min) the main effect is dilation of veins, coronary arteries, and pulmonary arterioles. Thus, low-dose nitroglycerin is useful in the treatment of myocardial ischemia, pulmonary hypertension, and congestive cardiac failure. By selectively dilating large coronary arteries, nitroglycerin, unlike sodium nitroprusside, does not cause coronary steal. At higher doses, systemic vasodilation becomes more prominent,33 which can result in hypotension and cause paradoxical worsening of myocardial ischemia. However, in patients with severe hypertension, nitroglycerin is often ineffective in controlling blood pressure.

The production of nitric oxide by the organic nitrates requires the presence of thio- compounds within the vascular endothelium. Infusing nitroglycerin for longer than 8 hours can cause depletion of these compounds, leading to reduced clinical effect.

Other than hypotension, the side effects of nitroglycerin are minimal. Reflex tachycardia can occur but is usually slight. There may be a dose-dependent fall in arterial oxygen saturation due to inhibition of hypoxic pulmonary vasoconstriction. The nitrite metabolites of nitroglycerin can lead to methemoglobinemia but it is not usually clinically significant.

Nitroglycerin

Nitroglycerin is a vasodilator with multiple uses in the cath lab. It is administered via the intra-arterial route to relieve coronary spasm and prevent spasm from intracoronary tools such as intravascular ultrasound catheters or coronary wires. Nitroglycerin relieves angina and heart failure by causing coronary dilatation and reducing preload and afterload.

Nitroglycerin can be administered via the intracoronary (IC), IV, transdermal, and sublingual route. Typical doses range from 50 to 300 mcg IC, 20–200 mcg/min IV, and 0.3 to 0.4 mg sublingual. Doses can be repeated until the desired effect is generated or hypotension develops. Tachyphylaxis can occur with chronic nitroglycerin use. Of note, nitroglycerin is not effective in vessels of less than 200 microns in diameter. Nitroglycerin therefore should not be used to treat no-reflow phenomenon unless there is superimposed epicardial vasospasm.