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Nitroglycerin

Class: Nitrates and Nitrites
VA Class: CV250
CAS Number: 55-63-0
Brands: GoNitro, Minitran, Nitro-Bid, Nitro-Dur, Nitrolingual, NitroMist, Nitrostat, Nitro-Time

Introduction

Nitroglycerin, an organic nitrate, is a vasodilating agent.

Uses for Nitroglycerin

Chronic Stable Angina

Management of angina pectoris secondary to CAD.600 802 806 807 809 810 811 817 823 1101

Short-acting preparations (e.g., sublingual nitroglycerin tablets, nitroglycerin spray) used for acute relief of angina; also may be usedb for acute prophylactic management in situations likely to provoke angina attacks.802 806 807 809 817 823 1101

Sublingual nitroglycerin is considered the drug of choice for acute relief of angina pectoris because it has a rapid onset of action, is inexpensive, and its efficacy is well established.b

Long-acting preparations (e.g., oral or topical nitroglycerin) used for long-term prophylactic management of chronic stable angina.600 810 811 1101

While β-blockers are recommended as the anti-ischemic drugs of choice in most patients with chronic stable angina, long-acting nitroglycerin preparations may be substituted or added in patients who do not tolerate or respond adequately to β-blockers.1101

Non-ST-Segment-Elevation Acute Coronary Syndromes (NSTE ACS)

Acute symptomatic relief of chest pain in patients with NSTE ACS, including unstable angina and non-ST-segment-elevation MI (NSTEMI).1100

Sublingual nitroglycerin (0.3–0.4 mg every 5 minutes for up to 3 doses) is recommended in patients with NSTE ACS who have continuing ischemic pain; IV nitroglycerin may be used in patients with heart failure, hypertension, or persistent ischemia not relieved with sublingual nitroglycerin and administration of a β-blocker.1100 Topical or oral nitrates may be an acceptable alternative to IV therapy in patients who do not have refractory or recurrent ischemia.1100

Acute MI

Management of patients with acute MI.217 218 240 241 242 527 808 812

Expert guidelines for the management of ST-segment-elevation MI (STEMI) state that IV nitroglycerin may be beneficial in patients with STEMI and heart failure or hypertension.527

Experts state there is no role for the routine use of oral nitrates during the convalescent phase of STEMI.527

Systemic hypotension with resultant worsening of myocardial ischemia is a potential complication of nitroglycerin therapy.236 Therefore, avoid use in patients with or at risk of hypotension.527

Avoid use in patients with marked bradycardia (e.g., <50 bpm) or tachycardia (e.g., >100 bpm)240 527 and those with suspected right ventricular infarction.241 527

Hypertension

IV nitroglycerin is used to control BP in perioperative hypertension, especially hypertension associated with cardiovascular procedures; to control BP in patients with severe hypertension or in hypertensive crises for the immediate reduction of BP in patients in whom such reduction is considered an emergency (hypertensive emergencies), especially those associated with coronary complications (e.g., coronary ischemia, acute coronary insufficiency, acute left ventricular failure, postoperative hypertension [especially following coronary bypass surgery]); and to produce controlled hypotension during surgical procedures.500 502 b

Heart Failure and Low-output Syndromes

IV nitroglycerin has been used in the management of acutely decompensated (e.g., congestive) heart failure and other low cardiac-output states.524

Current guidelines recommend a combination of drug therapies (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists) in adults with heart failure to reduce morbidity and mortality.524 701 703 800

IV vasodilators not shown to improve outcomes in patients hospitalized for heart failure; however, IV nitroglycerin may be considered as adjunct to diuretic therapy for relief of dyspnea in patients hospitalized for acutely decompensated heart failure who do not have symptomatic hypotension.524

Particularly useful in patients with heart failure and hypertension, coronary ischemia, or substantial mitral regurgitation.524

Tachyphylaxis may develop within 24 hours; some patients may develop resistance to even high doses.524

Cocaine-induced Acute Coronary Syndrome

Used adjunctively in the management of cocaine overdose to reverse coronary vasoconstriction and/or relieve hypertension or chest discomfort.696

Nitroglycerin Dosage and Administration

Administration

Administer lingually, sublingually, intrabuccally, orally, topically, or by IV infusion.b

Lingual, sublingual, or intrabuccal nitroglycerin may be inadequately absorbed, with resultant decreased efficacy, in patients with dry oral mucous membranes (e.g., xerostomia).219 220

Patient should be sitting immediately after lingual, sublingual, or intrabuccal administration of nitroglycerin.b

Lingual Administration

Administer nitroglycerin solution lingually using a metered-dose spray pump.807 The spray pump delivers 0.4 mg of nitroglycerin per metered spray.807 The 4.9-g lingual spray pump bottle usually delivers about 60 metered sprays; the 14.6-g bottle delivers about 200 metered sprays.807

Administer nitroglycerin aerosol lingually using a metered-dose spray container.806 The lingual aerosol container delivers 0.4 mg of nitroglycerin per metered spray.806 The 4.1-g aerosol container usually delivers about 90 metered sprays; the 8.5-g container delivers about 230 metered sprays.806

Prime (but do not shake) the spray pump or aerosol container prior to first use or after a period of nonuse (i.e., ≥6 weeks) according to the manufacturers' instructions.806 807

To administer the lingual aerosol or solution, hold the container or spray pump upright with the valve head uppermost and the spray orifice as close to the opened mouth as possible.806 807 To release a spray, press valve head with the forefinger.806 807 Spray lingual aerosol or solution onto or under tongue and immediately close mouth; do not inhale spray.806 807

Do not expectorate the drug nor rinse the mouth for 5–10 minutes following administration.806 807

Sublingual Administration

Sublingual tablets are dissolved under the tongue or in the buccal pouch.809 Do not swallow sublingual tablets.

Sublingual powder is dissolved under the tongue; do not swallow sublingual powder.823

Topical Administration (Transdermal System)

Apply nitroglycerin transdermal system topically to the skin as directed by manufacturer.811

Preferably apply at same time each day to areas of clean, dry, hairless skin of the upper arm or body; do not apply to extremities below knee or elbow.b

Avoid skin areas with irritation, extensive scarring, or calluses; rotate application sites to avoid skin irritation.b

Remove transdermal systems from site(s) of application prior to defibrillation or cardioversion since altered electrical conductivity and enhanced potential for electrical arcing may occur.205 206 207 210

Topical Administration (Ointment)

Apply topically using manufacturer-supplied applicator paper to measure dose.b

Spread on any non-hairy skin area (usually the chest or back) in a thin, uniform layer without massaging or rubbing; use applicator to prevent absorption through the fingers.b Tape applicator into place on skin.600

Application of the ointment over the chest may provide additional psychological effect.b

Some clinicians suggest avoiding placement of ointment on areas of chest where defibrillation paddles typically are placed due to potential for altered electrical conductivity.206

IV Administration

Administer via a controlled-infusion device that maintains a constant infusion rate.b

Because nitroglycerin readily migrates into many plastics, the manufacturers’ specific instructions for dilution, dosage, and administration must be carefully followed. 208

About 40–80% of the total amount of nitroglycerin in a diluted solution for IV infusion may be absorbed by the PVC tubing of IV administration sets in general use.b Special non-PVC plastic IV administration sets available that cause minimal drug absorption; when such sets are used, nearly all of the calculated dose of nitroglycerin is delivered to the patient.b

Administration through the same infusion set as blood can result in pseudoagglutination and hemolysis.208

Do not admix with other drugs.b

Dilution

Must dilute commercially available injection concentrate in 5% dextrose or 0.9% sodium chloride injection before administration.b

Dilute and store only in glass bottles; avoid using filters since some filters absorb nitroglycerin.b

Dosage

Carefully adjust dose according to the patient’s requirements and response; use smallest effective dosage.b

For IV administration, must consider the type of IV administration set used (PVC or non-PVC) in dosage estimations.b IV dosages commonly used in early published studies were based on the use of PVC administration sets and are too high when non-PVC administration sets are used.b

Relative hemodynamic and antianginal tolerance may develop during prolonged infusions, contributing to the need for careful dosage titration.b

Continuously monitor BP, heart rate, and other appropriate parameters (e.g., pulmonary capillary wedge pressure).b Must maintain adequate systemic BP and coronary perfusion pressure.b

Some patients with normal or low left ventricular filling pressures or pulmonary capillary wedge pressure may be extremely sensitive to the effects of IV nitroglycerin and may respond fully to dosages as low as 5 mcg/minute; these patients require particularly careful monitoring and dosage titration.b

Adults

Chronic Stable Angina
Acute Symptomatic Relief and Acute Prophylactic Management
Lingual

1 or 2 sprays (0.4 or 0.8 mg, respectively) as a lingual solution or aerosol at the onset of an attack.806 807

May give additional single sprays at intervals of approximately every 5 minutes as necessary if relief is not attained after initial spray(s);806 807 do not exceed 3 sprays in a 15-minute period.806 807

If pain persists after a total of 3 doses within a 15-minute period, seek prompt medical attention.806 807

If used prophylactically, may administer 5–10 minutes before situations likely to provoke angina attacks.806 807

Sublingual

Sublingual tablets: 0.3–0.6 mg at the first sign of an acute anginal attack.809 If relief not attained after a single dose, may give additional doses at 5-minute intervals.809 If pain persists after a total of 3 doses within a 15-minute period, or if the pain is different from that typically experienced, seek prompt medical attention.809

Sublingual powder: 1 or 2 packets (0.4 or 0.8 mg, respectively) at the onset of an attack.823 If relief is not attained after the initial dose, may administer an additional packet (0.4 mg) every 5 minutes as needed up to a total of 3 packets within a 15-minute period.823 If pain persists after a total of 3 packets within a 15-minute period, seek prompt medical attention.823

If used prophylactically, may administer a dose of nitroglycerin (as sublingual tablets or powder) 5–10 minutes before engaging in activities likely to provoke angina attacks.809 823

Long-term Prophylactic Management of Angina
Oral

Extended-release capsules: In clinical studies, initial dosage of 2.5–6.5 mg 3–4 times daily as an extended-release formulation has been administered, with subsequent titration based on patient response and adverse effects.810

To minimize occurrence of tolerance, a nitrate-free interval is recommended; however, minimum nitrate-free interval necessary with the extended-release capsules not known.810 Studies with other nitroglycerin formulations suggest that 10–14 hours may be sufficient.601

Do not use an extended-release formulation to treat acute attacks of angina; onset of action not sufficiently rapid.810

Topical (Transdermal System)

Initially, one transdermal dosage system applied every 24 hours, using system delivering the smallest available dose of nitroglycerin in its dosage series.b

Nitrate-free interval of 10–14 hours recommended to minimize occurrence of tolerance; however, the minimum nitrate-free interval necessary for restoration of full first-dose effects not determined.601 (See Tolerance and Dependence Under Cautions.)

May adjust dosage by changing to the next larger dosage system in the series or using a combination of dosage systems in the series.b

Do not use transdermal systems to treat acute attacks of angina.b

Topical (Ointment)

2% Ointment: Initially, 0.5 inch (approximately 7.5 mg), as squeezed from the tube, twice daily (once in the morning and repeat in 6 hours), suggested.600 601 When dose to be applied is in multiples of whole inches, may use unit-dose preparations that provide the equivalent of 1 inch of the 2% ointment.601

May double dose to 1 inch (approximately 15 mg) and subsequently double again to 2 inches (approximately 30 mg) if tolerated to achieve adequate response.600

Titrate dosage upward until angina is effectively controlled or adverse effects preclude further increases.b

Amount of nitroglycerin reaching the circulation varies directly with the size of application area and amount of ointment applied.b Generally, spread over an area approximately the size of the applicator (3.5 by 2.25 inches); however, may use a larger area (e.g., 6 by 6-inch area).600

To minimize the occurrence of tolerance to the effects of nitroglycerin, a nitrate-free interval of 10–14 hours has been recommended; however, the minimum nitrate-free interval necessary has not been determined.601 (See Tolerance and Dependence Under Cautions.)

Do not use ointment to treat acute attacks of angina.600

NSTE ACS
Sublingual, then IV (if necessary)

0.3–0.4 mg every 5 minutes for up to 3 doses as a sublingual preparation in patients with continuing ischemic pain.1100 Assess need for IV nitroglycerin, if not contraindicated.1100

IV

IV nitroglycerin may be useful in patients with heart failure, hypertension, or persistent ischemia not relieved with sublingual nitroglycerin and administration of a β-blocker.1100

Manufacturer states usual initial dosage is 5 mcg/minute when using a nonadsorptive (e.g., non-PVC) administration set; increase by 5 mcg/minute every 3–5 minutes until BP response is obtained or infusion rate is 20 mcg/minute.812 If no effect is obtained with 20 mcg/minute, may increase dosage by increments of 10 mcg/minute or, if necessary, by 20 mcg/minute.812 Higher dosages generally required when a PVC administration set is used; manufacturer states usual initial dosage is 25 mcg/minute with such administration sets.812 Titrate dosage according to patient's response.812

Continuously monitor BP and heart rate during administration.812

Acute MI
IV

Some experts recommend continuous IV infusion at an initial rate of 10 mcg/minute, increasing the dosage as necessary based on hemodynamic and clinical response.527 Dosage will vary considerably among patients; adjust based on individual requirements, BP response, and adverse effects.527 812

Manufacturer states usual initial dosage is 5 mcg/minute when using a nonadsorptive (e.g., non-PVC) administration set; increase by 5 mcg/minute every 3–5 minutes until BP response is obtained or infusion rate is 20 mcg/minute.812 If no effect is obtained with 20 mcg/minute, may increase dosage by increments of 10 mcg/minute or, if necessary, by 20 mcg/minute.812 Higher dosages generally required when a PVC administration set is used; manufacturer states usual initial dosage is 25 mcg/minute with such administration sets.812 Titrate dosage according to patient's response.812

Continuously monitor BP and heart rate during administration.812

Hypertension (Severe or Emergency)
IV

IV infusion dosage of up to 100 mcg/minute may be required, with effective dosages ranging from 5–100 mcg/minute.239

Once a partial BP response is obtained, reduce increases in dosage increments and lengthen interval between dosage increases.b

Hypotensive effect of IV nitroglycerin usually is apparent within 2–5 minutes and may persist for only several minutes (e.g., 3–5 minutes) once the infusion is discontinued if antihypertensive therapy (e.g., an oral agent) with a more prolonged duration has not been initiated.239

Always consider the risks of overly aggressive therapy in any hypertensive crisis.500 542

Initial goal of therapy for a hypertensive emergency is to reduce mean arterial BP by no more than 25% within minutes to 1 hour, followed by further reduction if stable toward 160/100 to 110 mm Hg within the next 2–6 hours, avoiding excessive declines in pressure that could precipitate renal, cerebral, or coronary ischemia.500

If this BP is well tolerated and the patient is clinically stable, can implement further gradual reductions toward normal BP in the next 24–48 hours; in patients with aortic dissection, should reduce systolic pressure to <100 mm Hg if tolerated.500 b

Special Populations

Hepatic Impairment

No specific dosage recommendations for hepatic impairment.b

Renal Impairment

No dosage adjustments necessary for renal impairment.809

Geriatric Patients

Cautious dosage selection, usually starting at the low end of the dosing range, because of possible age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.809

Cautions for Nitroglycerin

Contraindications

  • Known hypersensitivity to nitroglycerin, other nitrates or nitrites, or any ingredient in the formulation.806 807 809

  • Use of topical nitroglycerin (transdermal system) in those allergic to adhesives used in the system.811

  • Use of sublingual nitroglycerin tablets in patients with early MI, severe anemia, or increased intracranial pressure.809

    Use of extended-release oral nitrate preparations in patients with functional or organic GI hypermotility or malabsorption syndrome.c

  • Concomitant use of selective phosphodiesterase (PDE) inhibitors (e.g., sildenafil, tadalafil, vardenafil).809 c (See Selective Phosphodiesterase (PDE) Inhibitors under Cautions)

  • Concomitant use of soluble guanylate cyclase (sGC) stimulators (e.g., riociguat).806 807 823 (See Concomitant Use with sGC Stimulators under Cautions.)

Warnings/Precautions

Warnings

Concomitant Use with Selective Phosphodiesterase (PDE) Inhibitors

Selective PDE type 5 inhibitors can potentiate the hypotensive effects of organic nitrates and nitrites, possibly resulting in potentially life-threatening hypotension and/or hemodynamic compromise.809 c

PDE type 5 inhibitors (e.g., sildenafil, tadalafil, vardenafil) are contraindicated in patients receiving organic nitrates or nitrites in any form (e.g., orally, sublingually, transmucosally, parenterally), given regularly or intermittently,262 or nitric oxide donors since severe, potentially fatal hypotensive episodes can occur.260 261 262 263 266 271 272 282 284 285 288

Clinicians unfamiliar with their patients’ drug history, especially those involved in emergency care (e.g., for presumed MI or ischemia), should take a careful history so that concomitant use of organic nitrates or nitrites with selective PDE inhibitors can be avoided.260 264 271

Warn all patients receiving organic nitrates or nitrites about the potential interaction between the drugs and selective PDE inhibitors, even if they currently are not receiving the drugs, since there is substantial potential for patients to receive the drugs from another clinician, from a friend, with little or no clinical intervention (e.g., via the Internet),281 or illicitly.260 281 282

Warn all patients taking either selective PDE inhibitors or organic nitrates or nitrites of the potential consequences of taking the drugs within close proximity (e.g., within 24 hours of sildenafil; possibly more prolonged periods of risk with longer-acting PDE inhibitors) of taking a nitrate- or nitrite-containing preparation.260 282

Concomitant Use with sGC Stimulators

Concomitant use of nitrates (e.g., nitroglycerin) or nitrites (e.g., amyl nitrite) with a sGC stimulator (e.g., riociguat) can cause additive hypotensive effects.804 807 823 Such concomitant use is contraindicated.804 807 823 Time course and dose dependence of this interaction not established; use of these drugs within a few days of one another not recommended.823

Cardiovascular Effects

Severe hypotension, particularly in upright position, can occur even with low nitroglycerin doses, particularly in the elderly.807 809 811

Use with caution in patients who are volume depleted or have preexisting hypotension.807 809 811

Paradoxical bradycardia and angina exacerbation may accompany hypotension.807 809 811

Benefits in acute MI and CHF not established.811 If used in these conditions, careful clinical or hemodynamic monitoring for possible hypotension or tachycardia is recommended.811

Avoid long-acting dosage forms in the early management of acute MI or CHF since the effects are difficult to terminate rapidly should excessive hypotension or tachycardia occur.c

Sensitivity Reactions

Allergic reactions reported rarely.811 Contact dermatitis or fixed drug eruptions reported in patients receiving nitroglycerin ointment or transdermal system.811 Anaphylactoid reaction reported; possibly may occur with any route.811

General Precautions

Tolerance and Dependence

Tolerance to the vascular and antianginal effects of individual nitrates and cross-tolerance among the drugs may occur with repeated, prolonged use.809 c

Carefully individualize nitrate dosage to minimize the risk of tolerance; also consider potential risks of nitrate withdrawal.c

Intermittent dosing of nitrates (e.g., use of a nitrate-free interval of 10–14 hours daily) has been used in an attempt to minimize or prevent the development of tolerance to the hemodynamic and antianginal effects of the drugs.601 Consider the possibility of increased frequency or severity of angina during the nitrate-free interval.c

Possible cross-tolerance to sublingual nitroglycerin during long-term nitrate use.c

Nitrate dependence is possible (documented in daily industrial exposures); withdrawal manifestations (e.g., ischemic symptoms, MI, sudden death) can occur.c

Specific Populations

Pregnancy

Sublingual tablets: Category B.809 Sublingual nitroglycerin has been used for the treatment of angina during pregnancy without fetal harm.825

Lingual aerosol, lingual solution, ointment, transdermal system: Category C.600 806 807 811

Extended-release capsules, injection, sublingual powder: Data regarding pregnancy lacking.810 812 823

Some experts state that use of nitroglycerin during pregnancy does not appear to present a risk to the fetus; however, experience with the drug in pregnant women is limited.809 823 825 Use during pregnancy only if clearly needed.806 807 809

Lactation

Not known whether nitroglycerin is distributed into milk.809 The low molecular weight of nitroglycerin suggests that some distribution into milk may occur.825 Caution if used in nursing women.809

Pediatric Use

Safety and efficacy not established in pediatric patients.807 809 811

Geriatric Use

Clinical studies did not include sufficient numbers of individuals ≥65 years of age to determine whether they respond different than younger adults.809 811

Severe hypotension, particularly in upright position, can occur even with low nitroglycerin doses, particularly in the elderly.811 Geriatric patients may be more susceptible to hypotension and may be at greater risk of falling.811 Use with caution in geriatric patients who may be volume-depleted, are on multiple medications, or who, for whatever reason, already are hypotensive.811

May aggravate angina caused by hypertrophic cardiomyopathy, particularly in the elderly.807 811

Cautious dosage selection, usually starting at the low end of the dosing range, because of possible age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.809 811

Common Adverse Effects

Headache (pulsating or throbbing sensation, potentially severe); hypotension (may cause dizziness, weakness, other signs of cerebral ischemia); cutaneous vasodilation with transient flushing.807 809 811 c

Interactions for Nitroglycerin

Specific Drugs or Laboratory Tests

Drug or Test

Interaction

Comments

Alcohol

Concomitant use may cause hypotensionc

Use concomitantly with cautionc

Aspirin

High-dose aspirin (1 g) may increase exposure to nitroglycerin and enhance its vasodilatory and hemodynamic effects806 823

Antihypertensive drugs

Possible additive hypotensive effectsc

Dosage adjustment of either the nitrate/nitrite or the other agent with hypotensive activity may be necessary to avoid orthostatic hypotension during concomitant usec

Ergot alkaloids (dihydroergotamine)

Dihydroergotamine may counteract the coronary vasodilatory effect of nitrates303 316

Risk of angina precipitation316 806 807 823

Concomitant use not recommended316 806 807 823

Heparin

Because some,203 204 237 245 247 but not all,246 evidence indicates that IV nitroglycerin may antagonize the anticoagulant effect of heparin when these drugs are administered concomitantly, exercise caution203 204 237 245 247 812

Closely monitor patients receiving heparin and IV nitroglycerin concomitantly (e.g., measure APTT) to avoid inadequate anticoagulation203 204 236 237 245 246 247

If IV nitroglycerin therapy is discontinued in patients receiving heparin, reduction in heparin dosage may be necessary204 263 245 246 247

Nitrites

Observe patients receiving nitrates or nitrites concomitantly for possible additive hypotensive effectsc

Dosage adjustment of either the nitrate/nitrite or the other agent with hypotensive activity may be necessary to avoid orthostatic hypotension during concomitant usec

Phenothiazines

Possible additive hypotensive effectsc

Use concomitantly with caution; may need to adjust dosage to avoid orthostatic hypotension c

Phosphodiesterase (PDE) type 5 inhibitors (e.g., sildenafil, tadalafil, vardenafil)

Selective PDE type 5 inhibitors profoundly potentiate the vasodilatory effects (e.g., a >25-mm Hg decrease in SBP) of organic nitrates and nitrites (e.g., nitroglycerin, isosorbide dinitrate), and potentially life-threatening hypotension and/or hemodynamic compromise can result259 260 261 262 263 264 266 271 272 274 275 282 284 285

Combined use is contraindicated259 260 261 262 282 287

Some experts state that coadministration of PDE type 5 inhibitors with long-acting nitrates should be strictly avoided within 24 hours of nitrate administration; nitrates should not be taken for 24 hours after use of sildenafil or 48 hours after tadalafil1101

If a nitrate or nitrite is administered after a PDE inhibitor (e.g., >24 hours after sildenafil use), carefully monitor response to the initial doses and ensure proper facilities for fluid and vasopressor (e.g., α-adrenergic agonists) support are readily available260 289 334

Riociguat

Possible additive hypotensive effect804 807 823

Concomitant use contraindicated804 807 823

Test, Zlatkis-Zak color reaction

Nitrates and nitrites may interfere with the Zlatkis-Zak color reaction causing a false report of decreased serum cholesterolc

Thrombolytic agents

Concomitant administration of tissue-type plasminogen activator (t-PA) and IV nitroglycerin reduces plasma levels of t-PA and its thrombolytic effect806 823

Use concomitantly with caution806

Nitroglycerin Pharmacokinetics

Absorption

Bioavailability

Absorbed percutaneously through skin and oral mucosa.c

Topical (transdermal system) provides continuous, controlled release of nitroglycerin to the skin where the drug undergoes percutaneous absorption.b

Rates of delivery and absorption of nitroglycerin from transdermal systems vary depending on the specific preparation; consult the individual manufacturers’ information.b Preparations usually labeled in terms of the approximate rate of drug delivery per hour.b

Onset and Duration

The approximate onset and duration of action of various dosage forms of nitroglycerin are as follows:c

Antianginal Effects

Dosage Form

Onset

Duration

Sublingual

within 2 min

up to 30 min

Topical ointment

30 min

3 h

Oral extended-release

1 h327

up to 12 h327

Hemodynamic Effects

Dosage Form

Onset

Duration

Sublingual

2 min

up to 30 min

Topical ointment

within 1 h

3–6 h

Plasma Concentrations

Following topical application of transdermal system, steady-state plasma concentrations attained by about 2 hours;811 prolonged onset compared with other currently available dosage forms.b

Distribution

Extent

Widely distributed in the body.b

Unknown if nitroglycerin is distributed into milk.807 809 811

Plasma Protein Binding

Nitroglycerin: about 60% bound.b

Elimination

Metabolism

Metabolized to 1,3-glyceryl dinitrate, 1,2-glyceryl dinitrate, and glyceryl mononitrate.811 b

Glyceryl mononitrate, which is inactive, is the principal metabolite.b

Dinitrate metabolites are metabolized further to inactive mononitrates and are metabolized ultimately to glycerol and carbon dioxide.208

Extrahepatic sites of metabolism include red blood cells and vascular walls.208

Half-life

Nitroglycerin: 1–4 minutes.811 b

Stability

Handle undiluted nitroglycerin cautiously since it is a powerful explosive that can be exploded by percussion or excessive heat.b

Storage

Oral

Extended-release Capsules

Store at 25°C (may be exposed to 15–30°C); protect from moisture.810

Dispense in a tight container.810

Sublingual Powder

Store at 20–25°C (may be exposed to 5–40°C).823

Sublingual Tablets

Store in original glass container at 20–25°C.809

Advise patients to keep sublingual tablets in the original container and to close it tightly immediately after each use in order to prevent loss of potency.b

Lingual Aerosol

Store at 25°C (may be exposed to 15–30°C).806

Contains a highly flammable propellant (butane); do not forcefully open container, spray toward a flame, or place into a fire for disposal.806

Lingual Solution in Spray Pump

Store at 25°C (may be exposed to 15–30°C).807

Contains 20% alcohol; do not forcefully open container, spray toward a flame, or place into a fire or incinerator for disposal.807

Topical

Ointment

Tight containers at 20–25°C.600

Advise patients to tightly close multiple-dose containers of nitroglycerin ointment immediately after each use.600

Transdermal System

Sealed, single-dose containers at 15–30°C; avoid temperature extremes and/or humidity.b

Parenteral

IV Solutions

Concentrate for injection: store at 15–30°C; avoid freezing.b

Premixed solution in 5% dextrose injection: 25°C; avoid freezing and excessive heat.812

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Consult specialized references and the manufacturers’ labeling for specific stability and compatibility information, including IV containers and administration sets.b

Solution CompatibilityHID

Compatible

Dextrose 5% in Ringer’s injection, lactated

Dextrose 5% in sodium chloride 0.45 or 0.9%

Dextrose 5% in water

Ringer’s injection, lactated

Sodium chloride 0.45 or 0.9%

Sodium lactate 1/6 M

Drug Compatibility
Admixture CompatibilityHID

Compatible

Alteplase

Aminophylline

Dobutamine HCl

Dopamine HCl

Enalaprilat

Furosemide

Lidocaine HCl

Verapamil HCl

Incompatible

Hydralazine HCl

Phenytoin sodium

Variable

Bretylium tosylate

Dobutamine HCl with sodium nitroprusside

Y-Site CompatibilityHID

Compatible

Amiodarone HCl

Amphotericin B cholesteryl sulfate complex

Argatroban

Atracurium besylate

Bivalirudin

Dexmedetomidine HCl

Diltiazem HCl

Dobutamine HCl

Dobutamine HCl with dopamine HCl

Dobutamine HCl with lidocaine HCl

Dobutamine HCl with sodium nitroprusside

Dopamine HCl

Dopamine HCl with dobutamine HCl

Dopamine HCl with lidocaine HCl

Dopamine HCl with sodium nitroprusside

Drotrecogin alfa (activated)

Epinephrine HCl

Esmolol HCl

Famotidine

Fenoldopam mesylate

Fentanyl citrate

Fluconazole

Furosemide

Haloperidol lactate

Heparin sodium

Hetastarch in lactated electrolyte injection (Hextend)

Hydromorphone HCl

Inamrinone lactate

Labetalol HCl

Lidocaine HCl

Lidocaine HCl with dobutamine HCl

Lidocaine HCl with dopamine HCl

Lidocaine HCl with sodium nitroprusside

Linezolid

Lorazepam

Midazolam HCl

Milrinone lactate

Morphine sulfate

Nicardipine HCl

Norepinephrine bitartrate

Pancuronium bromide

Pantoprazole sodium

Propofol

Ranitidine HCl

Remifentanil HCl

Sodium nitroprusside

Sodium nitroprusside with dobutamine HCl

Sodium nitroprusside with dopamine HCl

Sodium nitroprusside with lidocaine HCl

Tacrolimus

Theophylline

Thiopental sodium

Tirofiban HCl

Vasopressin

Vecuronium bromide

Warfarin sodium

Incompatible

Alteplase

Lansoprazole

Levofloxacin

Variable

Hydralazine HCl

Actions

  • Principal pharmacologic property is relaxation of vascular smooth muscle, resulting in generalized vasodilation.c

  • Peripheral venous resistance is decreased via a selective action on venous capacitance vessels and results in venous pooling of blood and decreased venous return to the heart.c

  • Vasodilatory effect on arteriolar resistance is not as great as the action on the venous side; as a result of this combined action, both venous filling pressure (preload) and, to a lesser extent, arterial impedance (afterload) are reduced.c

  • By decreasing myocardial oxygen consumption, nitrates and nitrites alter the imbalance of myocardial oxygen supply and consumption which is thought to cause angina pectoris.236 250

  • Because of hemodynamic profile, nitrates and nitrites are particularly beneficial in patients with left ventricular systolic dysfunction or CHF.236 250

  • Both direct vasodilatory effects on the coronary bed and drug-induced prevention of episodic coronary artery vasoconstriction increase total coronary blood flow.236

  • After therapeutic doses, cardiac output may increase transiently and then decrease.c

  • In addition to vascular smooth muscle, nitrates and nitrites relax bronchial, biliary (including the gallbladder, biliary ducts, and sphincter of Oddi), GI (including the esophagus), ureteral, and uterine smooth muscle; also relax all smooth muscle irrespective of autonomic innervation and are functional antagonists of norepinephrine, acetylcholine, and histamine occurs.c

Advice to Patients

  • Advise patients of the likelihood of headache, particularly with initial nitrate therapy.c

  • Advise patients to take nitrates as directed, particularly since tolerance can occur.c

  • Advise patients to tightly close multiple-dose containers of nitroglycerin ointment immediately after each use.b

  • Importance of instructing patients to discard cotton from tablet bottle once the original container is opened.b

  • Importance of instructing patients to keep the sublingual tablets in the original container or in a supplemental container specifically labeled as being suitable for nitroglycerin tablets, and to close it tightly immediately after each use in order to prevent loss of potency.b

  • Importance of instructing patients receiving nitroglycerin for relief of acute attacks of angina pectoris to consult a clinician or go to a hospital emergency room immediately if chest pain is not relieved after 3 doses approximately every 5 minutes,527 817 1100 1101 because inability to relieve chest pain may indicate acute MI.c

  • Importance of clinicians unfamiliar with their patients’ drug history, especially those involved in emergency care (e.g., for presumed MI or ischemia), to take a careful history so that concomitant use with selective PDE inhibitors can be avoided.260 264 271

  • Importance of warning all patients receiving organic nitrates or nitrites about the potential interaction between the drugs and selective PDE inhibitors, even if they currently are not receiving the drugs, since there is substantial potential for patients to receive the drugs from another clinician, from a friend, with little or no clinical intervention (e.g., via the Internet),281 or illicitly.260 281 282

  • Importance of warning all patients taking either selective PDE inhibitors or organic nitrates or nitrites of the potentially severe and life-threatening hemodynamic consequences of taking the drugs within close proximity (e.g., within 24 hours of sildenafil; possibly more prolonged periods of risk with longer-acting PDE inhibitors) of taking a nitrate- or nitrite-containing preparation.260 282

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.809

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.809

  • Importance of informing patients of other important precautionary information.809 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Nitroglycerin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Lingual

Aerosol

0.4 mg/spray*

Nitroglycerin Aerosol

NitroMist

Mist

Solution

0.4 mg/spray*

Nitroglycerin Spray

Nitrolingual Pumpspray

Arbor

Oral

Capsules, extended-release

2.5 mg*

Nitroglycerin Capsules ER

Nitro-Time

Time-Cap

6.5 mg*

Nitroglycerin Capsules ER

Nitro-Time

Time-Cap

9 mg*

Nitroglycerin Capsules ER

Nitro-Time

Time-Cap

Parenteral

For injection concentrate, for IV infusion

5 mg/mL (50 mg)

Nitroglycerin Injection

Sublingual

Powder

0.4 mg/packet

GoNitro

Espero

Tablets

0.3 mg*

Nitroglycerin Tablets

Nitrostat

Pfizer

0.4 mg*

Nitroglycerin Tablets

Nitrostat

Pfizer

0.6 mg*

Nitroglycerin Tablets

Nitrostat

Pfizer

Topical

Ointment

2%

Nitro-Bid

Fougera

Transdermal System

0.1 mg/hour (total nitroglycerin content and transdermal system size may vary by manufacturer)*

Minitran

Valeant

Nitro-Dur

Merck

Nitroglycerin Transdermal System

0.2 mg/hour (total nitroglycerin content and transdermal system size may vary by manufacturer)*

Minitran

Valeant

Nitro-Dur

Merck

Nitroglycerin Transdermal System

0.3 mg/hour (60 mg/15 cm2)

Nitro-Dur

Merck

0.4 mg/hour (total nitroglycerin content and transdermal system size may vary by manufacturer)*

Minitran

Valeant

Nitro-Dur

Merck

Nitroglycerin Transdermal System

0.6 mg/hour (total nitroglycerin content and transdermal system size may vary by manufacturer)*

Minitran

Valeant

Nitro-Dur

Merck

Nitroglycerin Transdermal System

0.8 mg/hour (160 mg/40 cm2)

Nitro-Dur

Merck

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Nitroglycerin in Dextrose

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for IV use only

100 mcg/mL (25 or 50 mg) Nitroglycerin in 5% Dextrose*

Nitroglycerin in 5% Dextrose Injection

200 mcg/mL (50 mg) Nitroglycerin in 5% Dextrose*

Nitroglycerin in 5% Dextrose Injection

400 mcg/mL (100 or 200 mg) Nitroglycerin in 5% Dextrose*

Nitroglycerin in 5% Dextrose Injection

AHFS DI Essentials. © Copyright 2018, Selected Revisions October 30, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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