NITROGLYCERIN

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) Butane-1,2,3,4-tetrol Tetranitrate
2) Erythrol Nitrate
3) Erythritol tetranitrate
4) Erythrol Tetranitrate
5) Nitroerythrite
6) Nitroerythrol
7) Tetranitrin
8) Tetranitrol
9) CAS 7297-25-8

1) Dinitro sorbide
2) Sorbide nitrate
3) CAS 87-33-2

1) 1,2,3-Propanetriol trinitrate
2) Glonoin
3) Glyceryl Trinitrate
4) Trinitrin
5) Trinitroglycerin
6) Trinitroglycerol
7) NITROGLYCERIN MIXTURE WITH MORE THAN 2% BUT NOT MORE THAN 10% NITROGLYCERIN, DESENSITIZED
8) NITROGLYCERIN, LIQUID, UNDESENSITIZED
9) NITROGLYCERIN, LIQUID, NOT DESENSITIZED
10) NITROGLYCERIN, DESENSITIZER, WITH LESS THAN 40% PHLEGMATIZER, BY WEIGHT
11) NITROGLYCERIN, DESENSITIZED, WITH 40% OR MORE NON-VOLITILE WATER UNSOLUBLE PHLEGMATIZER, BY WEIGHT
12) NITRO-SPAN
13) NITRIDERM
14) NITROGLYCERIN SOLUTION
15) NITROGLYCERIN, LIQUID, DESENSITIZED
16) SPIRIT OF NITROGLYCERIN (NOT GREATER THAN 1% NITROGLYCERIN BY WEIGHT)
17) GLYCEROL TRINITRATE SOLUTION
18) GLYCERYL TRINITRATE SOLUTION
19) MILLITHROL
20) NITOCINE
21) NITRIC ACID TRIESTER OF GLUCEROL
22) MYCOGLYCERIN
23) SPIRITS OF NITROGLYCERIN
24) NITROGLYCERIN SOLUTION IN ALCOHOL, NOT MORE THAN 1% NITROGLYCERIN
25) SPIRIT OF NITROGLYCERIN (1 TO 10%)
26) SOLUTION OF GLYCERYL TRINITRATE
27) NITROL (PHARMACEUTICAL)
28) NITROGLYCERINE (FRENCH)
29) NITROGLYCERIN SOLUTION IN ALCOHOL, WITH MORE THAN 1% BUT NOT MORE THAN 5% NITROGLYCERIN
30) NITROGLYCERIN SOLUTION IN ALCOHOL, WITH 10% OR LESS BUT MORE THAN 1% NITROGLYCERIN
31) TRINITROGLYCERINE
32) CAS 55-63-0

1) 2,2-Bis((nitrooxy)-methyl)-1,3-propanediol dinitrate
2) Erynite
3) Niperyt
4) Nitropentaerythritol
5) Nitropenthrite
6) Pentaerythrityl tetranitrate
7) Penthrit
8) PETN
9) CAS 78-11-5

1.2.1) MOLECULAR FORMULA
1) ISOSORBIDE DINITRATE: C6H8N2O8
2) ISOSORBIDE MONONITRATE: C6H9NO6
3) NITROGLYCERIN: C3H5N3O9

Available Forms Sources

1) DRUG FORMULATIONS AND PRODUCTS

a) SUMMARY

1) Nitroglycerin products (eg, nitroglycerin, isosorbide dinitrate, isosorbide mononitrate) are organic nitrates that are available in a wide-array of formulations including: sublingual tablets, extended-release formulations, lingual aerosol, topical ointment, paste and transdermal patches, and intravenously.

b) NITROGLYCERIN

1) Generic Intravenous Solution: 5 mg/mL
2) Generic Extended-Release oral capsule: 2.5 mg, 6.5 mg, 9 mg
3) Sublingual tablet: 0.3 mg, 0.4 mg, 0.6 mg
4) Transdermal patch (Extended-Release): 0.1 mg/hr, 0.2 mg/hr, 0.4 mg/hr, and 0.6 mg/hr
5) Minitran: Transdermal Patch (Extended-Release): 0.1 mg/hr, 0.2 mg/hr, 0.4 mg/hr and 0.6 mg/hr
6) Nitro-bid: Topical ointment 2%
7) Nitro-bid: Transdermal patch 2%
8) Nitro-Dur: Transdermal Patch (Extended-Release): 0.1 mg/hr, 0.2 mg/hr, 0.3 mg/hr, 0.4 mg/hr, 0.6 mg/hr, and 0.8 mg/hr
9) Nitrolingual: Sublingual spray: 0.4 mg/actuation
10) NitroMist: Sublingual Spray: 0.4 mg/actuation
11) NitroQuick: Sublingual Tablet: 0.3 mg, 0.4 mg, 0.6 mg
12) NitroStat: Sublingual Tablet: 0.3 mg, 0.4 mg, 0.6 mg
13) Nitro-Time: Oral Capsule (Extended-Release): 2.5 mg, 6.5 mg, 9 mg

c) ISOSORBIDE DINITRATE

1) Generic Oral Tablets: 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg
2) Generic Extended-Release formulation: 40 mg
3) Generic Sublingual tablet: 2.5 mg, 5 mg
4) Dilatrate-SR (Extended-Release) oral capsule: 40 mg
5) IsoDitrate (Extended-Release) oral tablet: 40 mg
6) Isordil Titradose oral tablet: 5 mg, 10 mg, 40 mg

d) ISOSORBIDE MONONITRATE

1) Generic Oral Tablets: 10 mg, 20 mg
2) Generic Extended-Release formulation: 30 mg, 60 mg, 120 mg
3) Imdur ER (Extended-Release) oral tablet: 30 mg
4) Imdur (Extended-Release) oral tablet: 30 mg, 60 mg, 120 mg
5) Ismo oral tablet: 20 mg
6) Monoket oral tablet: 10 mg, 20 mg

e) TABLE OF TRADE NAMES

1) Trade Names for Nitroglycerin:

1) Ang-O-Span
2) Glyceryl trinitrate
3) Minitran
4) N-G-C
5) Niong
6) Nitro-Bid
7) Nitrobon
8) Nitrocap
9) Nitrocap T.D.
10) Nitrodisc
11) Nitro-Dur
12) Nitroglyn
13) Nitrek
14) Nitrol
15) Nitrolin
16) Nitrolingual
17) Nitro-Long
18) NitroMist
19) Nitronet
20) Nitrong
21) Nitrospan
22) Nitrostat
23) Nitrostat SR
24) Nitro-Time
25) Nitrotab
26) Sustachron
27) Transderm-Nitro
28) Trates
29) Tridil

2) Trade Names for Erythrityl Tetranitrate:

1) Cardilate
2) Erthyritol tetranitrate

3) Trade Names for Isosorbide Dinitrate:

1) Coronex
2) Dilatrate SR
3) Iso-Bid
4) Isochron
5) Isonate
6) Isonate TR
7) Isordil
8) Isotrate
9) Onset
10) Sorate
11) Sorbide T.D.
12) Sorbitrate
13) Sorbitrate SA

4) Trade Names for Isosorbide Mononitrate

1) Imdur
2) Imdur ER
3) Ismo
4) Monoket

2) INDUSTRIAL

a) Nitroglycerin is a viscous and oily liquid at room temperature (ACGIH, 2001; Baselt, 1997; Clayton & Clayton, 1994; Hathaway et al, 1996a; HSDB , 2000).
b) Nitroglycerin becomes a solid at temperatures below 56 degrees F (NIOSH , 2000). If forms triclinic or rhombic crystals (Clayton & Clayton, 1994; HSDB , 2000; ILO, 1998).
c) Nitroglycerin decomposes between 50 to 60 degrees C (ACGIH, 2001; Budavari, 1996; Lewis, 1996) or between 122 to 140 degrees F (NIOSH , 2000). It decomposes energetically above 145 degrees C (Urben, 1995).
d) No signs of decomposition were reported when trinitroglycerin was heated to 180 degrees C at 50 mmHg pressure. The autoignition temperature approximately coincides with the boiling point at 760 mmHg, which is 245 degrees C (Belyaev AF and Yuzefovich NA, 1940).
e) It is appreciably volatile at 100 degrees C (Budavari, 1996; Lewis, 1996).
f) Nitroglycerin has a pale yellow or brown color in commercial form (ACGIH, 2001; NIOSH , 2000; Hathaway et al, 1996a).
g) Nitroglycerin can be part of a mixture (with more than 2%, but not more than 10% nitroglycerin) in the form of a desensitized white solid (AAR, 1998).
h) Nitroglycerin can be in the form of a liquid solution - with less than 5 percent nitroglycerin in alcohol (AAR, 1998; ERG, 2000).

1) Nitroglycerin is prepared by the nitration of anhydrous glycerol with a cooled mixture of nitric and sulfuric (catalyst) acids while stirring, followed by separation of nitroglycerin by gravity, and subsequent passage of water and an alkaline soda solution (Ashford, 1994; Kohler & Meyer, 1993; Lewis, 1997).

1) MEDICINAL

a) Nitroglycerin is a smooth muscle relaxant. It is used in medicine as a tocolytic agent and a vasodilator for treatment of angina pectoris due to coronary artery disease (Prod Info nitroglycerin extended-release oral capsules, 2005).

2) INDUSTRIAL

a) Nitroglycerin is a high explosive. It is used by itself for this purpose in certain applications such as in oil well drilling (ACGIH, 2001; Lewis, 1997).
b) Since the 1920s, nitroglycerin has been commercially mixed with ethylene glycol dinitrate (also known as nitroglycol) at a 40:60 or 20:80 ratio to make dynamite (ACGIH, 2001; Baselt, 1997). It has gradually been replaced by ammonium nitrate in the production of dynamite and other explosives (ILO, 1998), such that the modern dynamite consists of 60% ammonium and sodium nitrate, 20% to 25% ethylene glycol dinitrate, 0 to 5% nitroglycerin, 10% dinitrotoluene and 3% nitrocellulose, together with some sawdust, chalk, and rhodamin (Zenz, 1994).
c) It is used with guncotton to make cordite and other smokeless powders (ACGIH, 2001).
d) A mixture with soluble guncotton at a ratio of 92 to 94:6 to 8 is used as a comparative explosive in determinations of relative weight strength. Such a mixture is one of the strongest commercial explosives and scarcely ever used as an explosive in practice due to the hazards (Kohler & Meyer, 1993).
e) Nitroglycerin is used in rocket propellants (ACGIH, 2001; Clayton & Clayton, 1994; Lewis, 1997).
f) Nitroglycerin is used in combating oil-well fires (ILO, 1998; Lewis, 1997).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Nitroglycerin is an organic nitrate that is used as a vasodilator to treat coronary artery disease and heart failure. It is used therapeutically in forms of tablets (sublingual and extended-release), lingual aerosol, transdermal and intravenously. It is also a high explosive and is used occasionally in the production of explosives, smokeless powders, rocket propellants and in combating oil well fires.
B) EPIDEMIOLOGY: Nitroglycerin is a commonly prescribed drug and poisoning is relatively uncommon. Occupational exposure mainly occurs via dermal or inhalational exposure.
C) PHARMACOLOGY: Its mechanism of action is stimulation of cGMP production, resulting in vascular smooth muscle relaxation. It relaxes veins at low doses and arteries at high doses.
D) TOXICOLOGY: Toxicology is an extension of pharmacologic effects. Nitroglycerin is a nitrate, which can be converted to nitrites in the GI tract leading to oxidation of hemoglobin, methemoglobinemia, which may be more common in infants.
E) WITH THERAPEUTIC USE

1) ADVERSE EFFECTS: Headache, dizziness, and mild orthostatic hypotension are common adverse effects associated with nitroglycerin. WITHDRAWAL: Abrupt cessation of medical or occupational exposure may cause angina.
2) INDUSTRIAL EXPOSURE (dermal and inhalation): nausea, vomiting, abdominal cramps, headache, confusion, delirium, bradypnea, bradycardia, paralysis, seizures, cyanosis, methemoglobinemia, circulatory collapse and death.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Headache, flushing and orthostatic hypotension with reflex tachycardia can occur.
2) SEVERE TOXICITY: Severe effects may include profound hypotension with tachycardia. Profound and prolonged hypotension can cause end-organ damage including cardiac ischemia, ischemic stroke, liver injury and renal failure. Fatalities are rare, but may occur after circulatory collapse and respiratory failure.

0.2.3)

A) WITH POISONING/EXPOSURE

1) Hypotension is common. Bradycardia may occur in predisposed patients; reflex tachycardia may occur. Death occurs secondary to circulatory collapse or respiratory failure.

0.2.4)

A) WITH POISONING/EXPOSURE

1) LOSS OF VISION: A transient loss of vision reportedly occurred before acute toxic effects from nitroglycerin exposure.
2) Miosis and corneal damage occurred after intravenous exposure.

0.2.5)

A) WITH POISONING/EXPOSURE

1) Hypotension secondary to peripheral vasodilation is common. Bradycardia may be noted due to a central noradrenergic effect.

0.2.6)

A) WITH POISONING/EXPOSURE

1) Respiratory difficulties and death may result from exposure.

0.2.8)

A) WITH POISONING/EXPOSURE

1) Nausea, vomiting, colicky pain, and diarrhea may occur following overdose.

0.2.9)

A) ANIMAL STUDIES: Hepatocellular carcinoma and cholangiofibrosis developed in rats chronically exposed to nitroglycerin in their diet.

0.2.13)

A) WITH THERAPEUTIC USE

1) Nitroglycerin is converted to nitrites in the body which may result in methemoglobinemia. Hemolysis and fever have been reported in G6PD deficient patients treated with isosorbide dinitrate.

0.2.14)

A) WITH THERAPEUTIC USE

1) Contact dermatitis is rarely reported following administration of the ointment or transdermal delivery formulations. Skin flushing is common.
2) Skin irritation may occur with transdermal products, the effects are rarely severe.

0.2.18)

A) WITH THERAPEUTIC USE

1) Initial symptoms may be followed by central nervous system disorders as intense as acute mania. Severe poisoning can result in confusion, pugnaciousness, hallucinations and maniacal manifestations.

0.2.20)

A) ISOSORBIDE DINITRATE, ISOSORBIDE DINITRATE AND HYDRALAZINE COMBINATION, and NITROGLYCERIN (brands, Nitro-Dur(R), Rectiv(TM), and Nitromist(R)) are classified as US FDA Pregnancy Category C. ISOSORBIDE MONONITRATE and the nitroglycerin brand, Nitrostat(R) are classified as Pregnancy Category B. There are no adequate and well-controlled studies of nitroglycerin use in pregnant women. In animal studies, dose-related increases in embryotoxicity (mummified pups) were observed in rabbits administered oral isosorbide dinitrate. Increased occurrences of diaphragmatic hernias with decreased hyoid bone ossification were observed among pups when maternal rats were fed a diet including up to 1% of nitroglycerin; however, the increase was not statistically significant. Developmental abnormalities of the musculoskeletal system have been reported in female rats exposed to intraperitoneal nitroglycerine and fetotoxicity has been reported with high dose dermal exposure to nitroglycerine. Isosorbide mononitrate exposures in pregnant rats resulted in stillbirths, decreased maternal weight gain, decreased motor activity, and impaired lactation.

0.2.21)

A) At the time of this review, human carcinogenicity studies have not been conducted.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Administer IV fluids for hypotension.

B) MANAGEMENT OF SEVERE TOXICITY

1) Administer activated charcoal (GI decontamination should be performed only in patients who can protect their airway or who are intubated). Severe hypotension may develop and require intravenous fluids and vasopressors. After inhalation exposure, move patient to fresh air and monitor for respiratory distress.

C) DECONTAMINATION

1) PREHOSPITAL: Administer activated charcoal if recent, substantial ingestion of a sustained-release formulation, and the patient is able to protect their airway. If dermal exposure, remove nitroglycerin ointment/paste or patch and wash the exposed area thoroughly with soap and water. GI decontamination is not effective after sublingual exposure and is unlikely to be useful for regular release formulations because of rapid absorption and a short half-life.
2) HOSPITAL: Administer activated charcoal if recent, substantial ingestion of a sustained-release formulation, and patient able to protect airway. If dermal exposure, remove nitroglycerin ointment/past or patch and was exposed area thoroughly with soap and water. GI decontamination is not effective after sublingual exposure and is unlikely to be useful for regular release formulations because of rapid absorption and short half-life.

D) AIRWAY MANAGEMENT

1) Perform early in patients with severe intoxication (eg, respiratory depression, severe hypotension).

E) ANTIDOTE

1) There is no antidote for nitroglycerin. Methylene blue is the antidote for methemoglobinemia.

F) HYPOTENSION

1) Obtain intravenous access. Initiate treatment with intravenous fluids. If hypotension persists, initiate pressors and titrate to a mean arterial pressure of at least 60 mmHg. Direct-acting pressors such as epinephrine and norepinephrine are preferred. Insert foley catheter and monitor urine output.

G) RESPIRATORY ARREST

1) Respiratory depression is uncommon and can be treated with intubation and mechanical ventilation.

H) TACHYCARDIA

1) Tachycardia is usually reflex tachycardia in the setting of hypotension and improves with administration of intravenous fluids.

I) METHEMOGLOBINEMIA

1) Initiate oxygen therapy. Treat with methylene blue if patient is symptomatic (usually at methemoglobin concentrations greater than 20% to 30% or at lower concentrations in patients with anemia, underlying pulmonary or cardiovascular disease). METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.

J) ENHANCED ELIMINATION PROCEDURE

1) Hemodialysis or hemoperfusion are not effective because of the large volume of distribution.

K) PATIENT DISPOSITION

1) HOME CRITERIA: Asymptomatic patients with inadvertent overdose may be monitored at home, however, patients may require evaluation for chest pain, if that is the reason for the inadvertent overdose.
2) OBSERVATION CRITERIA: Patients with deliberate ingestions and symptomatic patients should be sent to a health care facility for observation for at least 4 hours. With extended-release ISOSORBIDE MONONITRATE ingestion, patients should be observed for 6 to 10 hours as onset of effects may be delayed (Tmax for therapeutic doses is 3 to 4.5 hours)
3) ADMISSION CRITERIA: Patients with persistent hypotension or methemoglobinemia should be admitted to hospital. Patients with significant persistent hypotension or methemoglobinemia should be admitted to an intensive care unit.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (severe hypotension, or severe methemoglobinemia), or in whom the diagnosis is not clear.

L) PITFALLS

1) Failure to recognize nitroglycerin toxicity and/or methemoglobinemia. Ingestions are unlikely to result in severe toxicity, because of extensive first pass metabolism and short duration of action of most products; do not overtreat.

M) PHARMACOKINETICS

1) Nitroglycerin is well absorbed via dermal and sublingual routes. Oral bioavailability is poor as first pass effect is very high. A subcutaneous depo may remain and cause effects for days after removal of patch. Absorption is rapid, there is extensive hepatic metabolism and half-life is short (2 to 3 minutes for nitroglycerin, up to 60 minutes for isosorbide dinitrate). Volume of distribution is 2 to 4 L/kg. Tmax for immediate release tablets is an hour or less, for extended release formulation it is 3 to 4.5 hours.

N) DRUG INTERACTIONS

1) Use of selective phosphodiesterase inhibitors, such as sildenafil, tadalafil and vardenafil, can intensify the effect of nitroglycerin causing severe hypotension. Several "all natural" proprietary male enhancement supplements have been found to contain sildenafil and thus, may potentiate the effects of nitroglycerin.

O) DIFFERENTIAL DIAGNOSIS

1) Any entity that can cause hypotension with tachycardia, including sepsis, cyanide poisoning, other vasodilatory agents, and clonidine.

0.4.3)

A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.

0.4.5)

A) OVERVIEW

1) Nitroglycerin is well absorbed through the skin.
2) Remove nitroglycerin ointment or transdermal patch (if applicable), and wash the skin thoroughly with soap and water.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

1) Hypotension is common. Bradycardia may occur in predisposed patients; reflex tachycardia may occur. Death occurs secondary to circulatory collapse or respiratory failure.

3.3.4)

A) WITH POISONING/EXPOSURE

1) HYPOTENSION: Nitroglycerin lowers the blood pressure, with maximum depression occurring at approximately 4 minutes after exposure (Clayton & Clayton, 1993). Overdoses result in vasodilation causing hypotension (Schlafer & Stork, 2000).

3.3.5)

A) WITH POISONING/EXPOSURE

1) A reflex increase in heart rate may result in order to maintain cardiac output when hypotension occurs following an overdose (Schlafer & Stork, 2000).
2) Decreased heart rate may occur due to central noradrenergic effects (Schlafer & Stork, 2000).

Heent

3.4.1)

A) WITH POISONING/EXPOSURE

1) LOSS OF VISION: A transient loss of vision reportedly occurred before acute toxic effects from nitroglycerin exposure.
2) Miosis and corneal damage occurred after intravenous exposure.

3.4.3)

A) WITH POISONING/EXPOSURE

1) LOSS OF VISION: Historically, it was reported that a transient loss of vision occurred before acute toxic effects from nitroglycerin exposure (Grant & Schuman, 1993).
2) Miosis and corneal damage resulted from intravenous exposure to nitroglycerin (RTECS , 2000).

Cardiovascular

3.5.1)

A) WITH POISONING/EXPOSURE

1) Hypotension secondary to peripheral vasodilation is common. Bradycardia may be noted due to a central noradrenergic effect.

3.5.2)

A) VASODILATATION

1) WITH POISONING/EXPOSURE

a) The direct relaxation of vascular smooth muscle results in dilation of veins, arteries, arterioles and coronary vessels (Prod Info nitroglycerin extended-release oral capsules, 2005; Rabinowitch, 1944; RTECS , 2000; Schlafer & Stork, 2000). Circulatory collapse and death may result from toxic exposure (Prod Info nitroglycerin extended-release oral capsules, 2005; Schlafer & Stork, 2000).

B) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypotension and cardiovascular collapse may occur due to vasodilation, with increases in nitric oxide formation in vascular smooth muscle cells, resulting in increased intravascular volume and subsequent hypotension (Prod Info nitroglycerin extended-release oral capsules, 2005; Schlafer & Stork, 2000; Khan & Carleton, 1981; Ehrenpreis et al, 1989). Tolerance may result from chronic exposure.
b) CASE REPORT: An 80-year-old man, with multiple medical problems, developed prolonged, refractory hypotension and ultimately expired due to an unintentional "generous" application of 2% nitroglycerin ointment to a rash instead of Nystatin(R) ointment. Approximately 2 hours after application of nitroglycerin ointment the patient's blood pressure was 50 to 60 mmHg. Despite aggressive therapy with fluids and vasopressors, the patient's condition deteriorated and he expired (Schlafer & Stork, 2000).

C) SYNCOPE

1) WITH THERAPEUTIC USE

a) Syncope has been reported with therapeutic use of nitroglycerin (Prod Info NITROSTAT(R) oral tablets, 2000).

2) WITH POISONING/EXPOSURE

a) Syncope can occur following overdose (Prod Info NITROSTAT(R) oral tablets, 2000).
b) CASE REPORT: Lightheadedness, graying of vision, and loss of consciousness was observed in an 81-year-old woman as a result of inadvertent application of nitroglycerin ointment to her toothbrush (O'Keefe et al, 1986). The patient regained consciousness within several minutes with a severe headache which lasted 30 minutes. No adverse sequelae were observed. The patient had mistakenly utilized her husband's nitroglycerin ointment instead of her toothpaste. Buccal and gingival areas are considered excellent sites for nitrate absorption (especially with brushing or massaging), and it was felt that the patient may have received 10 times the standard transmucosal nitroglycerin dose.

D) BRADYCARDIA

1) WITH THERAPEUTIC USE

a) Bradycardia may occur in patients with sick sinus node syndrome or patients taking beta blocking drugs (Khan & Carleton, 1981).

2) WITH POISONING/EXPOSURE

a) Nitroglycerin may cause bradycardia due to a central noradrenergic effect (Schlafer & Stork, 2000). Heart block and bradycardia may develop following a significant exposure (Prod Info nitroglycerin extended-release oral capsules, 2005).
b) Bradycardia may occur in patients with sick sinus node syndrome or patients taking beta blocking drugs (Khan & Carleton, 1981).

E) TACHYARRHYTHMIA

1) WITH POISONING/EXPOSURE

a) A reflex increase in heart rate may result in order to maintain cardiac output when hypotension occurs following an overdose (Schlafer & Stork, 2000) .

F) MYOCARDIAL INFARCTION

1) WITH POISONING/EXPOSURE

a) Acute myocardial infarction due to coronary vasospasm has been described following withdrawal from industrial exposure to nitroglycerin (Przybojewski & Heyns, 1983).
b) RISK FACTORS: Individuals with preexisting ischemic heart disease should not be assigned to work where significant exposure to nitroglycerin may occur (Hathaway et al, 1996).

G) LEFT HEART FAILURE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Left ventricular function deteriorated in a 34-year-old man with alcoholic cardiomyopathy and liver dysfunction following 0.25 inch nitroglycerin paste applied to skin over abdomen spread over a 6-square-inch area. Pulsus Alternans began about 30 minutes after the nitroglycerin paste application and resolved shortly after nitroglycerin removal and leg elevation (Chandraratna et al, 1979).

H) DEAD

1) WITH POISONING/EXPOSURE

a) From 1965 to 1977, 9 deaths from cardio-cerebrovascular disease were observed versus 4.5 expected among men with at least 1 year exposure to dynamite and 20 years of induction-latency time. The unexposed were comparable with the national average (HSDB , 2000).

Respiratory

3.6.1)

A) WITH POISONING/EXPOSURE

1) Respiratory difficulties and death may result from exposure.

3.6.2)

A) ACUTE RESPIRATORY INSUFFICIENCY

1) WITH POISONING/EXPOSURE

a) Following a toxic ingestion, nitroglycerin can cause respiratory difficulties, hypoxia, and death due to respiratory paralysis (Prod Info nitroglycerin extended-release oral capsules, 2005). Exposure to high levels by inhalation or skin absorption can cause breathing difficulties and death (Sittig, 1991). Dyspnea and tachypnea may result if methemoglobinemia is a manifestation of toxicity (Prod Info nitroglycerin extended-release oral capsules, 2005; Dart et al, 2000).

Neurologic

3.7.2)

A) HEADACHE

1) WITH THERAPEUTIC USE

a) Headache is a frequently reported effect at therapeutic doses (Rabinowitch, 1944; Ehrenpreis et al, 1989). It may be an immediate and persistent event following sublingual use (Prod Info NITROSTAT(R) oral tablets, 2000)

2) WITH POISONING/EXPOSURE

a) Headache is a frequently reported event following overdose. Symptoms are described as a persistent, throbbing headache (Prod Info NITROSTAT(R) oral tablets, 2000; Rabinowitch, 1944; Ehrenpreis et al, 1989).

B) INCREASED TOLERANCE

1) WITH THERAPEUTIC USE

a) Patients receiving nitroglycerin continuously for more than 24 hours either by infusion or repeated sublingual dosing are at risk for developing tolerance (Prod Info NITROSTAT(R) oral tablets, 2000; Abrams et al, 1998).

2) WITH POISONING/EXPOSURE

a) TOLERANCE may develop with repeated exposure. A special aspect of tolerance has been observed among individuals exposed to nitroglycerin in the manufacture of explosives. They frequently suffer from headache, dizziness, and postural weakness during the first several days of employment. Tolerance then develops. This phenomenon is also observed in workers after a weekend away from exposure (HSDB , 2000).

C) DIZZINESS

1) WITH POISONING/EXPOSURE

a) Dizziness may occur as a result of vasodilatation (Prod Info NITROSTAT(R) oral tablets, 2000; Schlafer & Stork, 2000).

D) PERSONALITY DISORDER

1) WITH POISONING/EXPOSURE

a) ABNORMAL BEHAVIOR: Chronic exposure may result in clinical findings as listed above along with quarrelsome, destructive behavior most notably following concurrent ethanol ingestion (Rabinowitch, 1944).

E) TOXIC ENCEPHALOPATHY

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A case of Wernicke's encephalopathy has been reported in a 74-year-old patient on 1250 mcg/min, possibly due to ethanol and propylene glycol diluents (Shorey et al, 1984).

Gastrointestinal

3.8.1)

A) WITH POISONING/EXPOSURE

1) Nausea, vomiting, colicky pain, and diarrhea may occur following overdose.

3.8.2)

A) VOMITING

1) WITH POISONING/EXPOSURE

a) Nausea and vomiting may occur following overdose due to vasodilation (Prod Info NITROSTAT(R) oral tablets, 2000).
b) CASE REPORT: Following an accidental, "generous" application of nitroglycerin ointment instead of Nystatin(R) ointment for a topical fungal infection, an 80-year-old man vomited a large amount of bilious material (Schlafer & Stork, 2000).

B) DIARRHEA

1) WITH POISONING/EXPOSURE

a) Colicky pains and diarrhea may occur following overdose (Prod Info NITROSTAT(R) oral tablets, 2000; Rabinowitch, 1944).

Hepatic

3.9.1)

A) ANIMAL STUDIES: Hepatocellular carcinoma and cholangiofibrosis developed in rats chronically exposed to nitroglycerin in their diet.

3.9.3)

A) ANIMAL STUDIES

1) CARCINOMA

a) In rats, hepatocellular carcinoma and cholangiofibrosis were induced after exposure (through diet) to a dose of 1% of their body weight per day for 2 years (Clayton & Clayton, 1993).

Hematologic

3.13.1)

A) WITH THERAPEUTIC USE

1) Nitroglycerin is converted to nitrites in the body which may result in methemoglobinemia. Hemolysis and fever have been reported in G6PD deficient patients treated with isosorbide dinitrate.

3.13.2)

A) METHEMOGLOBINEMIA

1) WITH POISONING/EXPOSURE

a) Rarely, nitroglycerin toxicity causes an oxidant stress to iron bound hemoglobin, resulting in methemoglobinemia (Prod Info nitroglycerin transdermal system, 2005; Prod Info nitroglycerin extended-release oral capsules, 2005; Schlafer & Stork, 2000). These patients may have cyanosis not relieved by oxygen administration, a low pulse oximetry reading, and an arterial blood gas calculated saturation will be normal, while a measured saturation will be low. Nitroglycerin is converted to nitrites which have the ability to cause methemoglobinemia. High dose intravenous glyceryl trinitrate (10 to 58 mcg/kg/min) may result in methemoglobinemia (Gibson, 1982)(Bojar et al, 1987). Onset of action and toxic effect is greater via the intact skin and through mucous membranes than via the gastrointestinal route.
b) CASE REPORT: Methemoglobin of 7% was reported in an 80-year-old man following sublingual use of 100 of the 0.4 mg tablets over a 36-hour period. He also used 2% nitroglycerin ointment once daily and 10 mg of sublingual isosorbide dinitrate 4 times a day (Marshall & Ecklund, 1980).
c) CASE SERIES: Sublingual administration of 4.8 mg (12 of the 0.4 mg tablets) resulted in an insignificant rise in methemoglobin levels, to a maximum of 1.6%, in healthy volunteers (Paris et al, 1986).
d) ISOSORBIDE DINITRATE: Administration of 480 mg/day for 4 days to 6 patients with coronary heart disease had no effect on methemoglobin levels; single doses of 160 mg elevated levels to 1.13% after 2 hours (Schneider et al, 1984).

B) HEMOLYTIC ANEMIA

1) WITH POISONING/EXPOSURE

a) Isosorbide dinitrate has been reported to result in fever and hemolysis in G6PD-deficient patients.
b) CASE REPORT: Two G6PD deficient patients who were treated with isosorbide dinitrate developed fever, decreased hemoglobin, increased reticulocyte count, an increased bilirubin, an increase LDH, and a decreased haptoglobin concentration.

1) Fever and laboratory abnormalities cleared in both patients after discontinuation of the drug (Aderka et al, 1983).

3.13.3)

A) ANIMAL STUDIES

1) METHEMOGLOBINEMIA

a) In dogs, mild methemoglobinemia was induced after exposure to 25 mg/kg/day for 12 months (Clayton & Clayton, 1993).
b) In rats, methemoglobinemia was induced after exposure (through diet) to 1% of body weight per day for 2 years (Clayton & Clayton, 1993).
c) In mice, methemoglobinemia was induced after exposure (through diet) to 1000 mg/kg/day for 2 years (Clayton & Clayton, 1993).

Dermatologic

3.14.1)

A) WITH THERAPEUTIC USE

3.14.2)

A) FLUSHING

1) WITH POISONING/EXPOSURE

a) Skin flushing may commonly occur following overdose. The skin may be alternatively cold and clammy following a significant overdose (Prod Info nitroglycerin extended-release oral capsules, 2005; Ehrenpreis et al, 1989).

B) CONTACT DERMATITIS

1) WITH THERAPEUTIC USE

a) Allergic contact dermatitis has been reported rarely with ointment and transdermal drug delivery systems (Prod Info nitroglycerin transdermal system, 2005; Rosenfeld & White, 1984).

C) CHEMICAL BURN

1) WITH THERAPEUTIC USE

a) MICROWAVE BURNS: Patients treated with transdermal nitroglycerin systems (Transderm Nitro-10(R)) may be at risk of burns when exposed to microwave ovens (Murray, 1984).
b) CASE REPORT: A second-degree burn occurred in a patient exposed to a microwave oven with a leak. The burn coincided with the size and configuration of the Transderm nitro-10(R) patch.

Reproductive

3.20.1)

3.20.2)

A) ANIMAL STUDIES

1) ISOSORBIDE DINITRATE

a) RABBITS: Embryotoxicity (ie, increase in mummified pups) occurred with isosorbide dinitrate exposures 35 and 150 times the maximum recommended human dose (Prod Info isosorbide dinitrate oral tablets, 2013). These increases were also reported for rabbits at oral doses of isosorbide dinitrate 70 mg/kg (12 times the MRHD on a body surface area basis) (Prod Info BIDIL(R) oral tablets, 2013).

2) ISOSORBIDE MONONITRATE

a) RATS, RABBITS: No teratogenic effects were observed in pregnant rats and rabbits administered isosorbide mononitrate at doses up to 240 and 248 mg/kg/day (17 and 38 times, respectively the maximum recommended human doses based on body surface area) (Prod Info Isosorbide Mononitrate extended-release oral tablets, 2008).

3) NITROGLYCERIN

a) Nitroglycerin was not teratogenic in animal studies with transdermal, intraperitoneal, intravenous, topical, or oral administration. Studies in rats and rabbits revealed no toxic effects in dams or fetuses at any dose tested when nitroglycerin ointment was topically applied at doses up to 80 mg/kg/day and 240 mg/kg/day, respectively (Prod Info nitroglycerin in 5% dextrose intravenous injection, 2014; Prod Info NITRO-DUR(R) transdermal infusion system patch, 2014; Prod Info Nitrostat(R) sublingual tablets, 2011). In a study using the oral route, rats were fed a diet with nitroglycerin at levels up to 1% content (approximately 430 mg/kg/day) on days 6 to 15 of gestation. The pups of the high-dose group showed increased but not statistically significant occurrences of diaphragmatic hernias together with decreased hyoid bone ossification (Prod Info RECTIV(TM) intra-anal ointment, 2011; Prod Info NITROMIST(R) lingual aerosol, 2011)
b) There were no effects on fertility, or viability, growth or development of offspring in a three-generation study in rats given up to 38 mg/kg/day (Clayton & Clayton, 1993).
c) In female rats, dose of 220 mg/kg intraperitoneally produced developmental abnormalities of the musculoskeletal system; 3640 mg/kg dermally produced fetotoxicity (RTECS , 2000).

3.20.3)

A) LACK OF INFORMATION

1) At the time of this review, no data were available to assess the potential effects of exposure to these agents during pregnancy in humans:

a) ISOSORBIDE DINITRATE (Prod Info isosorbide dinitrate oral tablets, 2013)
b) ISOSORBIDE DINITRATE AND HYDRALAZINE COMBINATION (Prod Info BIDIL(R) oral tablets, 2013)
c) ISOSORBIDE MONONITRATE (Prod Info monoket(R) oral tablets, 2014)
d) NITROGLYCERIN (Prod Info nitroglycerin in 5% dextrose intravenous injection, 2014; Prod Info NITRO-DUR(R) transdermal infusion system patch, 2014; Prod Info Nitrostat(R) sublingual tablets, 2014; Prod Info RECTIV(TM) intra-anal ointment, 2011; Prod Info NITROMIST(R) lingual aerosol, 2011)

B) PREGNANCY CATEGORY

1) Isosorbide dinitrate, isosorbide dinitrate and hydralazine combination, and nitroglycerin brands Nitro-Dur(R), Rectiv(TM), and Nitromist(R) are classified as US FDA Pregnancy Category C (Prod Info isosorbide dinitrate oral tablets, 2013; Prod Info nitroglycerin in 5% dextrose intravenous injection, 2014; Prod Info NITRO-DUR(R) transdermal infusion system patch, 2014; Prod Info BIDIL(R) oral tablets, 2013; Prod Info ISORDIL(R) TITRADOSE(R) oral tablets, 2007; Prod Info RECTIV(TM) intra-anal ointment, 2011; Prod Info NITROMIST(R) lingual aerosol, 2011).
2) ISOSORBIDE MONONITRATE and the nitroglycerin brand, Nitrostat(R) are classified as Pregnancy Category B (Prod Info Nitrostat(R) sublingual tablets, 2014; Prod Info monoket(R) oral tablets, 2014).

C) RISK SUMMARY

1) NITROGLYCERIN

a) Data are limited on the effects of nitroglycerin use during pregnancy. In animal reproduction studies, no adverse developmental effects were noted after the IV administration to rabbits or intraperitoneal administration to rats during organogenesis at doses exceeding 64 times the human dose (Prod Info GONITRO(TM) sublingual powder, 2016).

D) ANIMAL STUDIES

1) ISOSORBIDE MONONITRATE

a) RATS: Offspring of rats exposed to doses of isosorbide mononitrate 540 mg/kg/day during late gestation and lactation showed a higher incidence of stillbirth, lower birth weights, and adverse effects on neonatal survival and development (Prod Info monoket(R) oral tablets, 2014).

2) NITROGLYCERIN

a) No embryotoxic or adverse developmental effects were noted after the transdermal application to pregnant rabbits and rats at doses up to 240 mg/kg/day for 13 days and intraperitoneal doses of 20 mg/kg/day administered to pregnant rats, or IV doses of 4 mg/kg/day administered to pregnant rabbits for 13 days (Prod Info GONITRO(TM) sublingual powder, 2016).
b) A nitroglycerin dose of 11 mg/kg intraperitoneally in female rats produced preimplantation mortality and fetal death (RTECS , 2000).

3.20.4)

A) LACK OF INFORMATION

1) ISOSORBIDE DINITRATE

a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation in humans (Prod Info isosorbide dinitrate oral tablets, 2013).

2) ISOSORBIDE DINITRATE AND HYDRALAZINE COMBINATION

a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation in humans (Prod Info BIDIL(R) oral tablets, 2013).

3) ISOSORBIDE MONONITRATE

a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation in humans (Prod Info monoket(R) oral tablets, 2014).

4) NITROGLYCERIN

a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation in humans (Prod Info GONITRO(TM) sublingual powder, 2016; Prod Info nitroglycerin in 5% dextrose intravenous injection, 2014; Prod Info NITRO-DUR(R) transdermal infusion system patch, 2014; Prod Info Nitrostat(R) sublingual tablets, 2014; Prod Info Nitrostat(R) sublingual tablets, 2011; Prod Info RECTIV(TM) intra-anal ointment, 2011; Prod Info NITROMIST(R) lingual aerosol, 2011).

3.20.5)

A) ANIMAL STUDIES

1) ISOSORBIDE DINITRATE

a) No altered fertility or gestation was observed in rats administered dietary isosorbide dinitrate doses of 25 or 100 mg/kg/day in a modified 2-litter reproduction study (Prod Info ISORDIL(R) TITRADOSE(R) oral tablets, 2007; Prod Info BIDIL(R) oral tablets, 2013).

2) ISOSORBIDE MONONITRATE

a) A reduced fertility index was seen in rats exposed to isosorbide mononitrate 360 mg/kg/day doses, though no effects on fertility were seen in 2 generations of rats with exposures up to 120 mg/kg/day (Prod Info monoket(R) oral tablets, 2014).

3) NITROGLYCERIN

a) Rats administered dietary nitroglycerin up to 434 mg/kg/day for 2 years developed dose-related interstitial cell tumors in the testes at an incidence of 52% versus 0% in the control group (Prod Info GONITRO(TM) sublingual powder, 2016).
b) A dominant lethal test in rats exposed through diet up to 363 mg/kg/day for 13 weeks showed no effect on male fertility (Clayton & Clayton, 1993).
c) In rats, interstitial cell tumors of the testes were induced after exposure, through diet, to 363 mg/kg/day (male) or 434 mg/kg/day (female) for 2 years (Clayton & Clayton, 1993).
d) Rats were administered dietary nitroglycerin at doses up to about 434 mg/kg/day for 6 months prior to mating in 1 generation, with treatment continuing through the next 2 generations in a reproduction study. While no effects on fertility were observed in the first generation, infertility that was attributed to increased interstitial cell tissue and aspermatogenesis in males administered high doses was reported for the 2 subsequent generations (Prod Info GONITRO(TM) sublingual powder, 2016; Prod Info NITRO-DUR(R) transdermal infusion system patch, 2014; Prod Info nitroglycerin in 5% dextrose intravenous injection, 2014; Prod Info Nitrostat(R) sublingual tablets, 2011; Prod Info RECTIV(TM) intra-anal ointment, 2011; Prod Info NITROMIST(R) lingual aerosol, 2011).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS55-63-0 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

B) IARC Carcinogenicity Ratings for CAS87-33-2 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

C) IARC Carcinogenicity Ratings for CAS78-11-5 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

D) IARC Carcinogenicity Ratings for CAS7297-25-8 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

3.21.2)

A) At the time of this review, human carcinogenicity studies have not been conducted.

3.21.3)

A) LACK OF INFORMATION

1) At the time of this review, human carcinogenicity studies have not been conducted. The carcinogenic potential of isosorbide dinitrate, isosorbide mononitrate, and nitroglycerin in humans is unknown (Prod Info NITRO-DUR(R) transdermal infusion system patch, 2014; Prod Info nitroglycerin in 5% dextrose intravenous injection, 2014; Prod Info monoket(R) oral tablets, 2014; Prod Info isosorbide dinitrate oral tablets, 2013).

3.21.4)

A) ISOSORBIDE MONONITRATE

1) RATS: There was no evidence of carcinogenicity in rats administered isosorbide mononitrate at doses up to 900 mg/kg/day for 6 months followed by 500 mg/kg/day for up to 121 weeks in males and 137 weeks in females (Prod Info monoket(R) oral tablets, 2014).

B) NITROGLYCERIN

1) Nitroglycerin is an equivocal tumorigenic agent by RTECS criteria (RTECS , 2000) with experimental tumorigenic data (Lewis, 1996).
2) RATS: Dose-related fibrotic and neoplastic changes in liver, including carcinomas and interstitial cell tumors in testes, were observed in rats that received up to 434 mg/kg/day of dietary nitroglycerin for 2 years. Incidences of hepatocellular carcinomas at high doses were 52% vs 0% in untreated controls. Incidences of testicular tumors were 52% vs 8% in controls (Prod Info NITRO-DUR(R) transdermal infusion system patch, 2014; Prod Info nitroglycerin in 5% dextrose intravenous injection, 2014; Prod Info Nitrostat(R) sublingual tablets, 2014).
3) RATS: Hepatocellular carcinoma and interstitial cell tumors of the testes were induced after dietary exposure to 363 mg/kg/day (male) or 434 mg/kg/day (female) for 2 years (Clayton & Clayton, 1993).

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs and mental status.
B) Serum nitroglycerine levels are not readily available or clinically useful.
C) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity.
D) Routine monitoring of electrolytes, renal function, glucose, pulse oximetry and blood gases may be helpful in patients with severe toxicity.
E) A methemoglobin concentration should be obtained, if clinically indicated (patient is cyanotic, short of breath, or has mental status changes). Pulse oximetry may be inaccurate and calculated oxygen saturation will be normal in presence of methemoglobinemia.
F) Other causes of tachycardia and hypotension should be ruled out.

4.1.2)

A) SERUM/CHEMISTRY

1) Routine monitoring of electrolytes, renal function, glucose, and blood gases may be helpful in patients with severe toxicity.

B) HEMATOLOGIC

1) In the presence of cyanosis, a methemoglobin level should be determined. When methemoglobinemia is present, a decreased pulse oximetry reading may be seen and an arterial blood gas calculated saturation may be read as normal. It is important to obtain an arterial blood gas with oxygen saturation determined by a co-oximeter (Schlafer & Stork, 2000).

4.1.4)

A) OTHER

1) MONITORING

a) Monitor vital signs and mental status in all overdose cases for signs of hypotension.
b) Monitor pulse oximetry in patients with severe toxicity.

2) ECG

a) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity

Methods

1) Plasma nitroglycerin may be assayed by electron-capture gas chromatography (Wei & Reid, 1979) and gas liquid chromatography (Noonan et al, 1984; Watari et al, 1986).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with persistent hypotension or methemoglobinemia should be admitted to hospital. Patients with significant persistent hypotension or methemoglobinemia should be admitted to an intensive care unit.

6.3.1.2) HOME CRITERIA/ORAL

A) Asymptomatic patients with inadvertent overdose may be monitored at home, however, patients may require evaluation for chest pain, if that is the reason for the inadvertent overdose.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (severe hypotension, or severe methemoglobinemia), or in whom the diagnosis is not clear.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with deliberate ingestions and symptomatic patients should be sent to a health care facility for observation for at least 4 hours. With extended-release ISOSORBIDE MONONITRATE ingestion, patients should be observed for 6 to 10 hours as onset of effects may be delayed (Tmax for therapeutic doses is 3 to 4.5 hours).

Monitoring

Oral Exposure

6.5.1)

A) SUMMARY

1) Administer activated charcoal if recent, substantial ingestion of a sustained-release formulation, and the patient is able to protect their airway. GI decontamination is not effective after sublingual exposure and is unlikely to be useful for regular release formulations, because of rapid absorption and a short half-life.

B) ACTIVATED CHARCOAL

1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

C) DERMAL EXPOSURE

1) If dermal exposure, remove nitroglycerin ointment/paste or patch and wash the exposed area thoroughly with soap and water.

6.5.2)

A) ACTIVATED CHARCOAL

1) Administer activated charcoal if recent, substantial ingestion of a sustained-release formulation, and patient able to protect airway. GI decontamination is not effective after sublingual exposure and is unlikely to be useful for regular release formulations because of rapid absorption and short half-life.
2) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

3) CHARCOAL DOSE

b) ADVERSE EFFECTS/CONTRAINDICATIONS

6.5.3)

A) SUPPORT

1) Treatment is based on symptomatic and supportive care. Treat hypotension initially with IV fluids. Severe hypotension may develop and require intravenous fluids and vasopressors. After inhalation exposure, move patient to fresh air and monitor for respiratory distress. Provide appropriate airway management, with administration of 100% oxygen.

B) HYPOTENSIVE EPISODE

1) Severe overdoses can result in vasodilation causing hypotension, and sometimes cardiovascular collapse and bradycardia due to central noradrenergic effects. Overdoses act in the CNS to cause central alpha-2 adrenergic stimulation and increase norepinephrine central activity. In most patients, hypotension responds to intravenous fluid administration. In patients with severe unresponsive hypotension, vasopressor therapy should be selected on the basis of receptor selectivity (Schlafer & Stork, 2000).

a) Appropriate choices would include agonist agents acting at peripheral alpha-1 adrenergic receptors without causing agonist effects at beta-2 adrenergic receptors. For bradycardic patients, beta-1 adrenergic agonism would be desired. Optimal choices for treating severe unresponsive hypotension, in decreasing order include: phenylephrine > norepinephrine and dopamine > epinephrine > dobutamine.

2) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

3) PHENYLEPHRINE

a) MILD OR MODERATE HYPOTENSION

1) INTRAVENOUS: ADULT: Usual dose: 0.2 mg; range: 0.1 mg to 0.5 mg. Maximum initial dose is 0.5 mg. A 0.5 mg IV dose can elevate the blood pressure for approximately 15 min (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011). PEDIATRIC: Usual bolus dose: 5 to 20 mcg/kg IV repeated every 10 to 15 min as needed (Taketomo et al, 1997).

b) CONTINUOUS INFUSION

1) PREPARATION: Add 10 mg (1 mL of a 1% solution) to 500 mL of normal saline or dextrose 5% in water to produce a final concentration of 0.2 mg/mL.
2) ADULT DOSE: To raise blood pressure rapidly; start an initial infusion of 100 to 180 mcg/min until blood pressure stabilizes; then reduce infusion to 40 to 60 mcg/min titrated to desired effect. If necessary, additional doses in increments of 10 mg or more may be added to the infusion solution and the rate of flow titrated to the desired effect (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011).
3) PEDIATRIC DOSE: Intravenous infusion should begin at 0.1 to 0.5 mcg/kg/min; titrate to the desired effect (Taketomo et al, 1997).

c) ADVERSE EFFECTS

1) Headache, reflex bradycardia, excitability, restlessness and rarely dysrhythmias may develop (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011).

4) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

5) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

C) METHEMOGLOBINEMIA

1) SUMMARY

a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.

2) METHYLENE BLUE

a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).

3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)

a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.

Inhalation Exposure

6.7.2)

A) SUPPORT

1) Treatment is symptomatic and supportive.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

6.8.1)

A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

6.9.1)

A) DERMAL DECONTAMINATION

1) Patients with topical exposure to nitroglycerin (powder, ointment/paste or transdermal delivery system) should have the substance removed and the area washed thoroughly with soap and water.

6.9.2)

A) SUPPORT

1) Treatment is symptomatic and supportive.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

1) Hemodialysis or hemoperfusion are not effective because of the large volume of distribution.

Abstracts

Case Reports

1) CASE REPORT: An 80-year-old man took 100 tablets of 0.4 mg nitroglycerin for a 36-hour period for episodes of chest pain. He had a history of angina pectoris and was prescribed isosorbide dinitrate, 10 mg sublingually 4 times a day; furosemide, 40 mg orally once daily; nitroglycerin 2% ointment, 2 inches at bedtime; and propranolol, 40 mg orally 4 times a day. He presented to a health care facility with chest pain and shortness of breath. A methemoglobin of 7% was found, with no history of cyanosis. ECG on admission showed diffuse ST-T changes, and a repeat tracing 4 hours later indicated an acute inferolateral myocardial infarction. The patient was treated with furosemide, morphine, and oxygen. Six hours after admission the patient developed hypotension (systolic BP, 70 to 80 mmHg) that failed to respond to fluids or dopamine. Severe bradycardia developed and cardiac arrest occurred. Resuscitation was not successful and the patient expired 8 hours after admission (Marshall & Ecklund, 1980).
2) CASE REPORT: A 74-year-old woman with glaucoma was transferred to the rehabilitation unit after repair of a cerebral aneurysm. During her stay she had an episode of flushing, headache, and presyncope. Physical exam was remarkable for a blood pressure of 90/60 mmHg. Neurologic exam and EKG were unchanged. Over the next two days, three similar episodes occurred. It was discovered that she had mistakenly applied nitroglycerin ointment, belonging to her roommate, to her chest and thighs instead of the lanolin cream prescribed for her. Comparison of the two products revealed identical box color and similar tube shape (Ehrenpreis et al, 1989).

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) SPECIFIC SUBSTANCE

1) ISOSORBIDE DINITRATE

a) TABLET: Usual starting dose is 5 mg to 20 mg 2 to 3 times daily; maintenance: 10 mg to 40 mg 2 to 3 times daily(Prod Info ISORDIL(R) TITRADOSE(R) oral tablets, 2007); dose-free interval of at least 14 hours/day recommended to minimize tolerance (Prod Info isosorbide dinitrate oral tablets, 2013)
b) SUBLINGUAL TABLET (5 mg, 10 mg, 20 mg, 30 mg and 40 mg): In patients that anticipate an activity may cause angina, the patient should take one sublingual tablet (2.5 to 5 mg) about 15 minutes before the activity. Based on large controlled studies with other nitrates, it is not expected that this formulation would provide more than 12 hours of continuous-antianginal activity per day. Sublingual tablets can stop acute angina episode, but it is usually only after a patient fails to respond to sublingual nitroglycerin (Prod Info ISORDIL(R) TITRADOSE(R) oral tablets, 2001).
c) EXTENDED-RELEASE (40 mg): The dosing varies by patient. Doses of 40 mg orally twice daily given every 6 hours have been used; maximum daily dose is 160 mg (Prod Info DILATRATE(R) SR sustained-release oral capsules, 2003).

2) ISOSORBIDE MONONITRATE

a) TABLETS: Usual recommended dose is 20 mg twice daily given 7 hours apart (Prod Info ISMO(R) oral tablets, 2006). For patients of particularly small stature, a starting dose of 5 mg (half of the 10-mg tablet) twice daily might be appropriate but should be increased to 10 mg or more by the second or third day of therapy, as 5-mg doses twice daily are effective for only the first day of treatment (Prod Info monoket(R) oral tablets, 2014).
b) EXTENDED RELEASE (30 mg, 60 mg and 120 mg): Usual starting dose is 30 mg or 60 mg once daily in the morning; after several days the dose may be increased to 120 mg once daily. Rarely, some patients may require 240 mg daily (Prod Info Isosorbide Mononitrate extended-release oral tablets, 2008).

3) NITROGLYCERIN

a) SUBLINGUAL TABLETS (0.3 to 0.6 mg): ACUTE ANGINA: Dissolve the tablet under the tongue or in the buccal pouch as needed at the start of acute angina. Repeat the dose every 5 minutes until pain is relieved. If pain persists after 3 tablets in a 15 minute period; prompt medical attention is recommended. PROPHYLACTIC: A dose may be administered 5 to 10 minutes before beginning an activity that may cause angina (Prod Info NITROSTAT(R) oral tablets, 2000).
b) EXTENDED-RELEASE CAPSULE (2.5 mg, 6.5 mg, 9 mg): PREVENTION OF ANGINA: Dose may vary by individual. In clinical trials, the initial regimen was 2.5 to 6.5 mg, 3 to 4 times daily. Adjust dose based on symptoms and side effects. In one study, 5 of 18 individuals were titrated up to a dose of 26 mg, 4 times daily (Prod Info nitroglycerin extended-release oral capsules, 2005).
c) LINGUAL AEROSOL (400 mcg/spray): ACUTE ANGINA: The lingual aerosol delivers 400 mcg/spray. One or 2 metered sprays should be administered on or under the tongue at the onset of an angina attack. No more than 3 sprays are recommended within a 15 min period. If chest pain persists, prompt medical attention is recommended. Do NOT inhale the spray (Prod Info NITROMIST(TM) lingual aerosol, 2006).
d) INTRAVENOUS: TREATMENT OF PERIOPERATIVE HYPERTENSION; CONTROL OF CONGESTIVE HEART FAILURE; ANGINA; INDUCTION OF INTRAOPERATIVE HYPERTENSION: Dilution concentration: 100, 200, or 400 mcg/mL in 5% dextrose. Initial dosage: 5 mcg/min through an infusion pump, using nonabsorptive tubing; titrate the dose based on clinical results, with initial titration in 5 mcg/min increments at 3- to 5-minute intervals. If no response is observed at 20 mcg/min, increments of 10 and later 20 mcg/min can be used. Once a partial hemodynamic response has occurred, the dose increase should be reduced and the interval between increases should be lengthened (Prod Info nitroglycerin in 5% dextrose intravenous injection, 2014).
e) OINTMENT (2% nitroglycerin ointment): PREVENTION OF ANGINA: Apply one-half inch to 2 inches of nitroglycerin ointment to the skin every 6 to 8 hours as needed during the day and at bedtime (Prod Info NITRO-BID(R) topical ointment, 2000).
f) TRANSDERMAL: PREVENTION OF ANGINA: Initial dose: 0.2 mg/hr and 0.4 mg/hr. Doses between 0.4 mg/hr and 0.8 mg/hr have been effective for 10 to 12 hours daily for at least 1 month. The dosing schedule is a daily patch on for a period of 12 to 14 hours and a daily patch-off period for 10 to 12 hours; this schedule is based on avoiding tolerance (Prod Info NITRO-DUR(R) transdermal infusion system patch, 2014; Prod Info nitroglycerin transdermal system, 2005).

7.2.2)

A) SPECIFIC SUBSTANCE

1) ISOSORBIDE DINITRATE

a) The safety and efficacy have not been established in pediatric patients (Prod Info isosorbide dinitrate oral tablets, 2013; Prod Info ISORDIL(R) TITRADOSE(R) oral tablets, 2007).

2) ISOSORBIDE MONONITRATE

a) The safety and efficacy have not been established in pediatric patients (Prod Info monoket(R) oral tablets, 2014; Prod Info Isosorbide Mononitrate extended-release oral tablets, 2008).

3) NITROGLYCERIN

a) The safety and efficacy have not been established in pediatric patients (Prod Info nitroglycerin in 5% dextrose intravenous injection, 2014; Prod Info NITRO-DUR(R) transdermal infusion system patch, 2014).
b) INTRAVENOUS

1) Studies in the literature used doses of 0.5 to 5 mcg/kg/min by IV infusion (Prod Info nitroglycerin in 5% dextrose intravenous injection, 2014).

Minimum Lethal Exposure

1) Toxicity is usually mild. The estimated adult oral lethal dose of nitroglycerin is 200 mg to 1200 mg (Prod Info nitroglycerin transdermal system, 2005).
2) The minimum lethal dose is not known. Doses of 1200 mg have been documented as survivable with no apparent ill effects (ACGIH, 2001). Certain individuals with hypertension are intolerant to nitroglycerin at concentration as low as 0.24 mg.
3) Methemoglobinemia may occur in severe poisonings with nitroglycerin (Schlafer & Stork, 2000). It is a rare event with organic nitrates. Methemoglobinemia should be suspected, if the patient develops impaired oxygen delivery despite adequate arterial PO2 (Prod Info NITROMIST(TM) lingual aerosol, 2006).
4) Insufficient data in the literature to accurately assess the minimal toxic/lethal dose of orally administered nitroglycerin. The severity of poisoning should be based on clinical findings.

Maximum Tolerated Exposure

1) The maximum tolerated dose is unknown for these various organic nitrates (Prod Info Isosorbide Mononitrate extended-release oral tablets, 2008; Prod Info ISORDIL(R) TITRADOSE(R) oral tablets, 2007; Prod Info NITROMIST(TM) lingual aerosol, 2006; Prod Info ISMO(R) oral tablets, 2006; Prod Info nitroglycerin extended-release oral capsules, 2005; Prod Info ISORDIL(R) TITRADOSE(R) oral tablets, 2001; Prod Info NITROSTAT(R) oral tablets, 2000)
2) Doses of 1200 mg have been reported as survivable with no apparent ill effects (ACGIH, 2001). It has been reported that over 75 ppm nitroglycerin can be immediately dangerous to life or health (HSDB , 2000). Certain individuals with hypertension are intolerant to nitroglycerin at concentration as low as 0.24 mg (Baselt, 1997).

1) A SUBLINGUAL dose of 4.8 mg resulted in hypotension and bradycardia in 1 of 12 healthy adult volunteers (Paris et al, 1986).
2) ORAL: Poisoning following oral ingestion is uncommon unless large doses have been ingested. There are insufficient data in the literature to assess the minimal toxic oral dose of nitroglycerin.
3) Acute oral ingestion of less than 25 of the 0.6 mg sublingual nitroglycerin tablets probably will not result in toxicity based on bioavailability of oral nitroglycerin. Assuming 1% bioavailability following an oral ingestion and an apparent volume of distribution of 3.3 L/kg, the estimated plasma concentration would be 4.5 ng/mL in a 10-kg child and 0.649 ng/mL in a 70-kg adult following an oral ingestion of 25 tablets containing 0.6 mg nitroglycerin/tablet. Toxicity may occur if significant absorption occurs in the oral cavity. Severity of intoxication following oral ingestion should be based on clinical findings.

Workplace Standards

1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.

a) Adopted Value

1) Nitroglycerin (NG)

a) TLV:

1) TLV-TWA: 0.05 ppm
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: Not Listed
2) Codes: Skin
3) Definitions:

a) Skin: This refers to the potential significant contribution to the overall exposure by the cutaneous route, including mucous membranes and the eyes, either by contact with vapors or, of likely greater significance, by direct skin contact with the substance. It should be noted that although some materials are capable of causing irritation, dermatitis, and sensitization in workers, these properties are not considered relevant when assigning a skin notation. Rather, data from acute dermal studies and repeated dose dermal studies in animals or humans, along with the ability of the chemical to be absorbed, are integrated in the decision-making toward assignment of the skin designation. Use of the skin designation provides an alert that air sampling would not be sufficient by itself in quantifying exposure from the substance and that measures to prevent significant cutaneous absorption may be warranted. Please see "Definitions and Notations" (in TLV booklet) for full definition.

c) TLV Basis - Critical Effect(s): Vasodilation
d) Molecular Weight: 227.09

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

B) ACGIH TLV Values for CAS87-33-2 (American Conference of Governmental Industrial Hygienists, 2010):

1) Not Listed

C) ACGIH TLV Values for CAS78-11-5 (American Conference of Governmental Industrial Hygienists, 2010):

1) Not Listed

D) ACGIH TLV Values for CAS7297-25-8 (American Conference of Governmental Industrial Hygienists, 2010):

1) Not Listed

E) NIOSH REL and IDLH Values for CAS55-63-0 (National Institute for Occupational Safety and Health, 2007):

1) Listed as: Nitroglycerine
2) REL:

a) TWA:
b) STEL: 0.1 mg/m(3)
c) Ceiling:
d) Carcinogen Listing: (Not Listed) Not Listed
e) Skin Designation: [skin]

1) Indicates the potential for dermal absorption; skin exposure should be prevented as necessary through the use of good work practices and gloves, coveralls, goggles, and other appropriate equipment.

f) Note(s):

3) IDLH:

a) IDLH: 75 mg/m3
b) Note(s): Not Listed

F) NIOSH REL and IDLH Values for CAS87-33-2 (National Institute for Occupational Safety and Health, 2007):

1) Not Listed

G) NIOSH REL and IDLH Values for CAS78-11-5 (National Institute for Occupational Safety and Health, 2007):

1) Not Listed

H) NIOSH REL and IDLH Values for CAS7297-25-8 (National Institute for Occupational Safety and Health, 2007):

1) Not Listed

I) Carcinogenicity Ratings for CAS55-63-0 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed ; Listed as: Nitroglycerin (NG)
2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Nitroglycerine
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

J) Carcinogenicity Ratings for CAS87-33-2 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

K) Carcinogenicity Ratings for CAS78-11-5 :

L) Carcinogenicity Ratings for CAS7297-25-8 :

M) OSHA PEL Values for CAS55-63-0 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Listed as: Nitroglycerin
2) Table Z-1 for Nitroglycerin:

a) 8-hour TWA:

1) ppm: 0.2

a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.

2) mg/m3: 2

a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.

3) Ceiling Value: (C) - An employee's exposure to this substance shall at no time exceed the exposure limit given.
4) Skin Designation: Yes
5) Notation(s): Not Listed

N) OSHA PEL Values for CAS87-33-2 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Not Listed

O) OSHA PEL Values for CAS78-11-5 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Not Listed

P) OSHA PEL Values for CAS7297-25-8 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Not Listed

Toxicity Information

7.7.1)

A) References: ITI, 1995 Lewis, 1996 RTECS, 2000

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 104 mg/kg -- caused ataxia and dyspnea and lowered body temperature

2) LD50- (ORAL)MOUSE:

a) 115 mg/kg

3) LD50- (SKIN)MOUSE:

a) Greater than 35.2 mg/kg

4) LD50- (SUBCUTANEOUS)MOUSE:

a) 110 mg/kg -- decreased general activity

5) LD50- (INTRAPERITONEAL)RAT:

a) 102 mg/kg -- caused ataxia and dyspnea and lowered body temperature

6) LD50- (ORAL)RAT:

a) 105 mg/kg -- decreased general activity

7) LD50- (SKIN)RAT:

a) Greater than 29.2 mg/kg

8) LD50- (SUBCUTANEOUS)RAT:

a) 94 mg/kg -- decreased general activity

Pharmacology Toxicology

Pharmacologic Mechanism

1) Organic nitrates, once inside the cells, may undergo metabolic activation to nitric oxide via catalytic facilitation by sulfhydryl compounds. Tolerance to nitrates is thought be a result of intracellular depletion of sulfhydryl donors.
2) Vasodilatation may then occur as a result of reaction by guanylate cyclase.

Toxicologic Mechanism

1) When tablets are swallowed rapidly they cause little toxicity as the drug is metabolized in the liver rapidly - this is unlike exposure to mucous membranes where drug does not pass through liver before entering general circulation.

1) A potential for hypotension and bradycardia due to central noradrenergic effects of nitroglycerin also exists. Nitroglycerin mimics the baroreceptor reflex, in the CNS, through penetration into nucleus tractur solitarii, resulting in central alpha-2 adrenergic stimulation and increases in norepinephrine central activity.

Physicochemical

Ph

Molecular Weight

Physical Characteristics

1) Nitroglycerin solubility in water: slightly soluble (ACGIH, 2001; Ashford, 1994; Clayton & Clayton, 1994); almost insoluble (Baselt & Cravey, 1995; Kohler & Meyer, 1993); 0.1% (at 68 degrees F) (NIOSH , 2000); 1800 mg/L (at 25 degrees C) (HSDB , 2000).
2) Nitroglycerin is soluble in oxygenated, aromatic, and chlorinated solvents. It is miscible with or soluble in benzene, ether, acetone, glacial acetic acid, nitrobenzene, pyridine, ethylene bromide, dichloroethylene, chloroform, and ethyl acetate (ACGIH, 2001; Ashford, 1994; Budavari, 1996; Clayton & Clayton, 1994; HSDB , 2000; ITI, 1995; Lewis, 1996).
3) Nitroglycerin is sparingly soluble in petroleum ether, liquid petrolatum, and glycerol (Budavari, 1996; Lewis, 1996).
4) Nitroglycerin is soluble in carbon disulfide - 1 g of nitroglycerin dissolves in 120 g of carbon disulfide (Budavari, 1996).
5) Nitroglycerin is soluble in alcohol (Clayton & Clayton, 1994); 1 gram dissolves in 4 g of ethanol (Budavari, 1996); 1 gram dissolves in 18 g of methanol (Budavari, 1996).
6) Nitroglycerin has a melting point of 13 degrees C (Ashford, 1994; Clayton & Clayton, 1994; ILO, 1998; Sittig, 1991); 13.1 degrees C (ITI, 1995); 13.5 degrees C - stable form (Budavari, 1996); 2.8 degrees C - labile form (Budavari, 1996).

1) Nitroglycerin becomes a solid at temperatures below 56 degrees F (NIOSH , 2000). It forms triclinic or rhombic crystals (Clayton & Clayton, 1994; HSDB , 2000; ILO, 1998).
2) Nitroglycerin decomposes between 50 to 60 degrees C (ACGIH, 2001; Budavari, 1996; Lewis, 1996) or between 122 to 140 degrees F (NIOSH , 2000).
3) Nitroglycerin decomposes energetically above 145 degrees C (Urben, 1995).
4) Nitroglycerin is appreciably volatile at 100 degrees C (Budavari, 1996; Lewis, 1996).

Animal Toxicology

References

General Bibliography

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NITROGLYCERIN

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Hematologic

Dermatologic

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Workplace Standards

Toxicity Information

Pharmacologic Mechanism

Toxicologic Mechanism

Ph

Molecular Weight

Physical Characteristics

General Bibliography