Nitroglycerin

Class: Nitrates and Nitrites
VA Class: CV250
CAS Number: 55-63-0
Brands: Minitran, Nitro-Bid, Nitro-Dur, Nitrogard, Nitrolingual Pumpspray, Nitrostat, Nitrotab, Nitrek, Nitro-Time

Introduction

Nitroglycerin, an organic nitrate, is a vasodilating agent.

Uses for Nitroglycerin

Angina

Acute relief of angina pectoris secondary to CAD;^{a b d} acute prophylactic management in situations likely to provoke angina attacks;^{a b d} and long-term prophylactic management of angina pectoris.^{b e}

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 Lingual or intrabuccal nitroglycerin and the other rapidly acting nitrates and nitrites (amyl nitrite inhalation and sublingual or chewable isosorbide dinitrate) also may be useful for acute relief.

In situations likely to provoke angina attacks, lingual, sublingual, or intrabuccal nitroglycerin or sublingual or chewable isosorbide dinitrate (no longer commercially available in the US) is effective.^b

Conventional measures in the management of angina pectoris are aimed at reducing the frequency, duration, and severity of attacks, and include coronary risk reduction (e.g., discontinuance of smoking, weight control, antilipemic strategies) rest, avoidance of precipitating circumstances (e.g., eating heavy meals, getting emotionally upset, performing strenuous exercise, exposure to cold air) and, if possible, treatment of the underlying cause.^c

β-Adrenergic blocking agents generally are considered among the initial antianginal drugs of choice in the long-term prophylactic management of chronic stable angina with or without prior MI to reduce symptoms and to prevent MI and/or death.²⁵⁸

Nitrates also used for acute symptomatic relief of unstable angina and for long-term prophylactic management of unstable angina.^{276 277 278 279 280}

Initial therapy for the treatment of patients presenting with symptoms suggestive of acute unstable angina includes aspirin, heparin, nitrates, and β-adrenergic blocking agents.^{276 277 278 280}

High-risk patients with persistent symptoms (ongoing or recurrent pain) or ECG changes suggesting ongoing ischemia may benefit from IV nitroglycerin, unless contraindicated; nitrates may be particularly useful in patients with coexisting hypertension or pulmonary edema.^{276 277 278 280} Once the patient’s clinical condition has stabilized for 24–48 hours, topical or oral nitrates may be used for control of recurrent unstable angina.²⁸⁰

AMI

Management of patients with AMI.^{216 217 218 236 240 241 242 339} Nitroglycerin is one of the principal initial therapies of MI.^{216 217 218 236 240 241 242 339}

Has been used to alleviate ischemia-induced pain, manage hypertension, and manage pulmonary congestion.³³⁹

IV infusion of nitroglycerin provides more precise minute-to-minute control of the hemodynamic effects of the drug than does sublingual or transdermal administration.^{236 217 218 236 242} Because of its onset of action, ease of titration, and opportunity for prompt termination if adverse effects occur, IV administration of the drug generally is preferred during the early stage of acute MI.²³⁶ Once the patient is hospitalized, sublingual nitroglycerin can be continued or transdermal therapy initiated.^{236 217 218 236 242}

Inadvertent systemic hypotension with resultant worsening of myocardial ischemia is a potential complication of nitroglycerin therapy.²³⁶ Therefore, while most patients should receive sublingual nitroglycerin to relieve ischemic-type chest pain, those with an initial SBP <90 mm Hg (or >30 mm Hg below baseline) generally should not receive nitrates.^{236 339}

Nitrates should be avoided in patients with marked bradycardia (e.g., <50 bpm) or tachycardia (e.g., >100 bpm),^{236 240 339} and should be used with extreme caution, if at all, in patients with suspected right ventricular infarction or inferior wall MI with possible right ventricular involvement.^{236 241 339}

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]); for the treatment of ischemic pain, CHF, or pulmonary edema associated with AMI; for the treatment of angina pectoris in patients who have not responded to recommended dosages of nitrates and/or a β-adrenergic blocking agent; and to produce controlled hypotension during surgical procedures.^{339 b}

Hypertensive emergencies are those rare situations requiring immediate BP reduction, although not necessarily to normal ranges, in order to prevent or limit target organ damage.²³⁹

Elevated BP alone, in the absence of symptoms or new or progressive target organ damage, rarely is a hypertensive crisis requiring emergency therapy.²³⁹

If IV nitroglycerin is used in the management of a hypertensive emergency, the initial goal of such therapy 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.²³⁹

Heart Failure and Low-output Syndromes

Nitroglycerin has been used in the management of heart failure and low-output syndromes† associated with AMI, and along with norepinephrine, dopamine, and dobutamine, is a preferred therapy.²³⁶

Cocaine-induced Acute Coronary Syndrome

Used in the management of cocaine overdose† to reverse coronary vasoconstriction.^{328 339}

AHA Advanced Cardiovascular Life Support (ACLS) committee considers nitroglycerin and benzodiazepines (e.g., diazepam, lorazepam) first-line agents in the management of drug-induced acute coronary syndrome.³³⁹

Nitroglycerin Dosage and Administration

Administration

Administer lingually, sublingually, intrabuccally, orally, topically, or by IV infusion.^{b 339}

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.^d

Spray pump must be primed (but not shaken) prior to first use or after a period of nonuse (i.e., ≥6 weeks) by actuating 1 spray.^d

Lingual spray delivers 0.4 mg of nitroglycerin per metered spray.^d The 4.9-g lingual spray pump bottle usually delivers about 60 metered sprays;^d the 12-g bottle delivers about 200 metered sprays.^d

Discard the spray pump once the maximum number of sprays is delivered.^b

Hold the lingual spray pump upright with the valve head uppermost and the spray orifice as close to the opened mouth as possible to administer.^d To release a spray, the valve head is pressed with the forefinger.^d

Dose is preferably sprayed onto or under the tongue and then the mouth immediately closed;^d the spray should not be inhaled and avoid swallowing immediately after the spray is administered.^b

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

Sublingual Administration

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

Intrabuccal Administration

Place extended-release tablets for buccal (transmucosal) administration on the oral mucosa between the lip and gum above the upper incisors or between the cheek and gum.^b Allow to dissolve undisturbed over a 3- to 5-hour period.^b

Extended-release buccal tablets should not be placed under the tongue and should not be chewed or swallowed.^b

Do not administer the extended-release buccal tablet at bedtime because of the risk of aspiration.^b

Topical Administration (Transdermal System)

Apply transdermal system containing nitroglycerin topically to the skin as directed by the manufacturer.^e

Transdermal system is preferably applied at the same time each day to areas of clean, dry, hairless skin of the upper arm or body; the units should not be applied to the extremities below the knee or elbow.^b

Skin areas with irritation, extensive scarring, or calluses should be avoided; application sites should be rotated to avoid causing skin irritation.^b

Transdermal systems should be removed from the site(s) of application prior to attempting defibrillation or cardioversion since altered electrical conductivity and enhanced potential for electrical arcing may occur.^{205 206 207 210 339}

Topical Administration (Ointment)

Apply topically using an applicator paper supplied by the manufacturers to measure the dose.^b

The dose-to-area ratio should be kept relatively constant (e.g., 1 inch on an area of 2 by 3 inches, 2 inches on an area of 3 by 4 inches, 3 inches on an area of 4 by 5 inches); when the dose is doubled, the area over which the ointment is applied should also be doubled.^b

Amount of nitroglycerin reaching the circulation varies directly with the size of the area of application and the amount of ointment applied.^b

Spread on any non-hairy skin area (usually the chest or back) in a thin, uniform layer without massaging or rubbing and using the applicator to prevent absorption through the fingers.^b

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

Nitroglycerin ointment has been reported to alter electrical conductivity, and some clinicians suggest that the ointment not be placed on areas of the chest where defibrillation paddles typically are placed.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 IV administration sets are available which are non-PVC plastic and 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

Commercially available injection must be diluted 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, the type of IV administration set used (PVC or non-PVC) must be considered 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 339}

Continuously monitor BP and heart rate, as well as other appropriate parameters (e.g., pulmonary capillary wedge pressure) in all patients.^b Adequate systemic BP and coronary perfusion pressure must be maintained.^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

Angina

Acute Symptomatic Relief and Acute Prophylactic Management

Lingual

Lingual solution using metered pump sprayer: 1 or 2 sprays (0.4 or 0.8 mg, respectively) onto or under the tongue; immediately close mouth.^d

Additional single sprays may be given at intervals of approximately every 3–5 minutes as necessary if relief is not attained after the initial spray(s);^b maximum of 3 sprays (1.2 mg) should be given in a 15-minute period.^d

If pain persists after a total of 3 doses within a 15-minute period, prompt medical attention is recommended.^b

If used prophylactically, spray may be used 5–10 minutes before situations likely to provoke angina attacks.^d

Sublingual

Sublingual tablets: 0.3–0.6 mg is placed under the tongue or in the buccal pouch and allowed to dissolve.^a

If relief is not attained after a single dose during an acute attack, additional doses may be given at 5-minute intervals.^a

If pain persists after a total of 3 doses within a 15-minute period, prompt medical attention is recommended.^a

If used prophylactically, place under the tongue or in the buccal pouch 5–10 minutes prior to engaging in activities likely to provoke angina attacks.^a

Intrabuccal

Extended-release buccal (transmucosal) tablets: place in buccal pouch and allow to dissolve undisturbed over a 3- to 5-hour period.^b

If an angina attack occurs while a tablet is currently in place, another tablet may be administered on the opposite side from the one already in place.^b

If an extended-release buccal tablet does not provide prompt relief of an acute attack, use of sublingual nitroglycerin is recommended.^b

If a tablet is inadvertently swallowed, another tablet may be administered as a replacement.^b

Treatment in Patients Unresponsive to Sublingual Nitroglycerin and β-adrenergic Blocking Agents

IV

Non-PVC administration set: 5 mcg/minute initially, with increases of 5 mcg/minute every 3–5 minutes until a blood pressure response is obtained or until the infusion rate is 20 mcg/minute. If no effect is obtained with 20 mcg/minute, dosage may be increased by increments of 10 mcg/minute and, if necessary, by increments of 20 mcg/minute.^b

PVC administration sets: 25 mcg/minute initially; then titrate dosage according to the response and tolerance of the patient.^b Generally requires higher dosages than non-PVC administration sets.^b

Long-term Prophylactic Management of Angina

Intrabuccal

Extended-release buccal (transmucosal) tablets: initially 1 mg 3 times daily given every 5 hours during waking hours, with the patient’s response assessed over a period of 4–5 days; titrate dosage upward incrementally until angina is effectively controlled or adverse effects preclude further increases.^b

Maintenance: 2 mg 3 times daily with a dosing interval of 3–5 hours.^b

If angina occurs while a tablet is in place, the dose should be increased to the next tablet strength; if angina occurs after a tablet has dissolved, the dosing frequency should be increased.^b

Oral

Extended-release capsules: 2.5–9 mg as an extended-release formulation has been administered orally every 8 or 12 hours.^b

Do not use an extended-release formulation to treat acute attacks of angina because the onset of action of extended-release nitroglycerin formulations is not sufficiently rapid to abort acute attacks of angina.³²⁷

Topical (Transdermal System)

Usual initial dosage is 1 transdermal dosage system, delivering the smallest available dose of nitroglycerin in its dosage series, applied every 24 hours.^b

To minimize the occurrence of tolerance to the effects of nitroglycerin, a nitrate-free interval of 10–12 hours has been recommended; however, the minimum nitrate-free interval necessary for restoration of full first-dose effects of nitrate therapy has not been determined.^b (See Tolerance and Dependence Under Cautions.)

Dosage may be adjusted by changing to the next larger dosage system in the series or by a combination of dosage systems in the series.^b

The transdermal systems should not be used to treat acute attacks of angina.^b

Topical (Ointment)

A suggested initial dosage is 0.5 inch, as squeezed from the tube, of the 2% ointment (i.e., approximately 7.5 mg) every 8 hours.^b

Generally, spread over an area approximately equivalent to 3.5 by 2.25 inches or greater.^b

Response to treatment is then assessed over the next several days.^b

Dosage should be titrated upward until angina is effectively controlled or adverse effects preclude further increases.^b

If angina occurs while the ointment is in place, the dose should be increased (e.g., in 0.5-inch increments).^b

If angina occurs after the ointment has been in place for several hours, the frequency of dosing should be increased.^b

Smallest effective dose should be administered 3 or 4 times daily, unless the patient’s clinical response suggests a different regimen.^b

When the dose to be applied is in multiples of whole inches, unit-dose preparations that provide the equivalent of 1 inch of the 2% ointment may also be used.^b

AMI

IV

Continuous IV infusion at a rate of 10–20 mcg/minute, increasing the dosage further in 5- to 10-mcg/minute increments at 5- to 10-minute intervals as necessary according to hemodynamic and clinical response.³³⁹

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, increases in dosage increments should be reduced and the interval between dosage increases should be lengthened.^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.²³⁴

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.²³⁹

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

Prescribing Limits

Adults

Angina

Acute Symptomatic Relief and Acute Prophylactic Management

Sublingual

No more than 3 doses in a 15- to 30- minute period.^b

Intrabuccal

No more than 3 doses in a 15- to 30- minute period.^b

Special Populations

Hepatic Impairment

No specific dosage recommendations for hepatic impairment.^b

Renal Impairment

No dosage adjustments necessary for renal impairment.^a

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.^a

Cautions for Nitroglycerin

Contraindications

• 
  

  Known hypersensitivity to nitroglycerin or any ingredient in the formulation.^{a d e}

  
  


• 
  

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

  
  


• 
  

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

  
  

  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).^{a c} (See Selective Phosphodiesterase (PDE) Inhibitors under Cautions)

  
  

Warnings/Precautions

Warnings

Selective Phosphodiesterase (PDE) Inhibitors

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

Manufacturers of selective PDE inhibitors (e.g., sildenafil, tadalafil, vardenafil) state that the drugs 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}

Cardiovascular Effects

Severe hypotension, particularly in upright position, can occur even with low nitroglycerin doses, particularly in the elderly.^{a d e}

Use with caution in patients who are volume depleted or have preexisting hypotension.^{a d e}

Paradoxical bradycardia and angina exacerbation may accompany hypotension.^{a d e}

Benefits in AMI and CHF not established.^e If used in these conditions, careful clinical or hemodynamic monitoring for possible hypotension or tachycardia is recommended.^e

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

Sensitivity Reactions

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

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.^{a c d d}

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 10–12 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.^c Consider the possibility of increased frequency or severity of angina during the nitrate-free interval.^c

Possible cross-tolerance to sublingual nitroglycerin during chronic 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

Category C.^{a d e}

Lactation

Not known whether nitroglycerin distributed into milk.^{a d e} Caution if used in nursing women.^{a d e}

Pediatric Use

Safety and efficacy not established in pediatric patients.^{a d e}

Geriatric Use

Clinical studies did not include sufficient numbers of individuals ≥65 years of age to determine whether they respond different than younger adults.^{a e}

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

May aggravate angina caused by hypertrophic cardiomyopathy, particularly in the elderly.^{d e}

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.^{a e}

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.^{a c d e}

Interactions for Nitroglycerin

Specific Drugs or Laboratory Tests

Drug or Test	Interaction	Comments
Alcohol	Concomitant use may cause hypotensionc	Use concomitantly with cautionc
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	Use concomitantly with caution; risk of angina precipitation
Heparin	Because some,203 204 236 237 245 247 but not all,236 246 evidence indicates that IV nitroglycerin may antagonize the anticoagulant effect of heparin when these drugs are administered concomitantly, caution should be exercised203 204 236 237 245 247	Patients receiving heparin and IV nitroglycerin concomitantly should be monitored (e.g., measurement of APTT) closely 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	Patients receiving nitrates or nitrites concomitantly should be observed 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) inhibitors, selective	Sildenafil and other selective PDE inhibitors (e.g., tadalafil, vardenafil) 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	Because of the serious risk of concurrent use of organic nitrates or nitrites and selective PDE inhibitors, such combined use is contraindicated259 260 261 262 282 287 339 If consideration is given to administering a nitrate or nitrite after a PDE inhibitor (e.g., >24 hours after sildenafil use), the response to the initial doses must be monitored carefully and proper facilities for fluid and vasopressor (e.g., α-adrenergic agonists) support must be readily available to prevent acute ischemic episodes260 289
Test, Zlatkis-Zak color reaction	Nitrates and nitrites may interfere with the Zlatkis-Zak color reaction causing a false report of decreased serum cholesterolc

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
Buccal (transmucosal) extended-release	within 2–3 min	3–5 h
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
Buccal (transmucosal) extended-release	within 2 minutes	up to at least 3 h
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;^e 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.^{a d e}

Plasma Protein Binding

Nitroglycerin: about 60% bound.^b

Elimination

Metabolism

Metabolized to 1,3-glyceryl dinitrate, 1,2-glyceryl dinitrate, and glyceryl mononitrate.^{b e}

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.^{b e}

Stability

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

Storage

Oral

Sublingual Tablets and Extended-release Capsules and Tablets

Dispense in the original, unopened container, preferably of glass, and stored at 15–30°C.^b

Discard cotton once the original container is opened.^b

Do not use tablets that are >12 months old; throw away any medication that is outdated or no longer needed.^med

Advise patients to keep 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

Lingual Solution in Spray Pump

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

Contains 20% alcohol; container should not be forcefully opened, sprayed toward a flame, or placed into a fire or incinerator for disposal.^d

Topical

Ointment

Tight containers at 15–30°C.^b

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

Transdermal System

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

Parenteral

IV Solutions

Concentrate for injection should be stored at 15–30°C; avoid freezing.^b

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 Compatibility^HID

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