Nitroglycerine

C01D - Vasodilators used in cardiac diseases ATC C01DA02

JFDA label: Deponit NT Transdermal

Indications

Approved

Intra-anal administration (Rectiv ointment)
Intravenous (IV) administration

Off-label

Esophageal spastic disorders
Gastroesophageal variceal hemorrhage
Short-term management of pulmonary hypertension (IV)
Sympathomimetic vasopressor extravasation injury (alternative to phentolamine)
Uterine relaxation

Contraindications

Source: Lexicomp

Additional contraindications for transdermal patch (not in US labeling): Acute circulatory failure associated with marked hypotension (shock and states of collapse) Absolute
Additional contraindications for translingual product (not in US labeling): Closed angle glaucoma Absolute
Hypersensitivity to nitroglycerin, other nitrates or nitrites, or any component of the formulation (includes adhesives for transdermal product) Absolute
acute circulatory failure or shock (Nitrolingual only) Absolute
concurrent use with phosphodiesterase-5 (PDE-5) inhibitors (avanafil, sildenafil, tadalafil, or vardenafil) Absolute
concurrent use with soluble guanylate cyclase (sGC) stimulators (eg, riociguat). Additional contraindications for IV product: Hypersensitivity to corn or corn products (solutions containing dextrose) Absolute
constrictive pericarditis Absolute
early myocardial infarction (sublingual tablet only Absolute
heart failure (aortic or mitral stenosis, constrictive pericarditis or hypertrophic obstructive cardiomyopathy) Absolute
increased intracranial pressure Absolute
increased intraocular pressure Absolute
myocardial infarction Absolute
myocardial insufficiency due to obstruction (eg, presence of aortic or mitral stenosis or of constrictive pericarditis) Absolute
orthostatic hypotension Absolute
pericardial tamponade Absolute
restrictive cardiomyopathy Absolute
severe anemia Absolute
severe anemia Additional contraindications for translingual product: Increased intracranial pressure Absolute
severe anemia. Note: According to the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines of the management of ST-elevation myocardial infarction (STEMI) and the ACC/AHA guidelines for the management of patients with non-ST-elevation acute coronary syndromes (NSTE-ACS), avoid nitrates in the following conditions: Hypotension (SBP Absolute
uncorrected hypovolemia Additional contraindications for sublingual product and rectal ointment: Acute circulatory failure or shock (sublingual tablets and powder) Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (7)

Common Hypotension · peripheral edema · syncope

Not Known Bradycardia · exacerbation of angina pectoris · flushing · orthostatic hypotension

Nervous system disorders (2)

Common Dizziness · paresthesia

Gastrointestinal disorders (2)

Common Abdominal pain

Not Known Vomiting

Skin and subcutaneous tissue disorders (1)

Not Known Diaphoresis

Musculoskeletal and connective tissue disorders (1)

Common Weakness

General disorders and administration site conditions (1)

Not Known Drug tolerance

Other (1)

Very Common Central nervous system: Headache

Respiratory, thoracic and mediastinal disorders (3)

Common Dyspnea · pharyngitis · rhinitis

Dosing

Source: Lexicomp

Note: Nitronal IV solution has been discontinued in the US for more than 1 year. Note: Hemodynamic and antianginal tolerance often develop within 24 to 48 hours of continuous nitrate administration. Nitrate-free interval (10 to 12 hours/day) is recommended to avoid tolerance development; gradually decrease dose in patients receiving nitroglycerin for prolonged period to avoid withdrawal reaction. Acute decompensated heart failure (off-label dose): IV: Initial: 10 to 20 mcg/minute, with subsequent titration (eg, 10 to 20 mcg/minute every 5 to 15 minutes) up to 200 mcg/minute (Coons 2011; Mebazaa 2016) or 0.3 to 0.5 mcg/kg/minute with titration (if SBP ≥90 mm Hg) in increments of 20 mcg/minute every 1 to 3 minutes up to 400 mcg/minute (Levy 2007). Patients who do not respond hemodynamically with doses of ~200 mcg/minute should be considered non-responders (Coons 2011). Angina/coronary artery disease: Oral: Initial: 2.5 to 6.5 mg 3 to 4 times daily; may titrate up to 26 mg 4 times daily IV: Manufacturer's labeling: 5 mcg/minute, increase by 5 mcg/minute every 3 to 5 minutes to 20 mcg/minute. If no response at 20 mcg/minute, may increase by 10 to 20 mcg/minute every 3 to 5 minutes (generally accepted maximum dose: 400 mcg/minute) Alternate dosing: ACCF/AHA guidelines for STEMI: Initial: 10 mcg/minute, with subsequent titration to desired blood pressure effect (ACCF/AHA [O'Gara 2013]). Sublingual powder (0.4 mg/packet): Manufacturer's labeling: 1 to 2 packets under tongue every 5 minutes as needed for maximum of 3 packets in 15 minutes; may also use prophylactically 5 to 10 minutes prior to activities which may provoke an angina attack Alternate dosing: ACCF/AHA guidelines for STEMI and AHA/ACC guidelines for the management of NSTE-ACS: 0.4 mg every 5 minutes up to 3 doses. Patients should be advised to take 1 dose promptly in response to chest pain. If pain is unrelieved or worsened 3 to 5 minutes after 1 dose, the patient or caregiver should call 9-1-1 immediately (ACC/AHA [Amsterdam 2014]; ACCF/AHA [O'Gara 2013]). Sublingual tablet: Manufacturer's labeling: 0.3 to 0.6 mg every 5 minutes for maximum of 3 tablets in 15 minutes; may also use prophylactically 5 to 10 minutes prior to activities which may provoke an attack. Alternate dosing: ACCF/AHA guidelines for STEMI and AHA/ACC guidelines for the management of NSTE-ACS: 0.3 to 0.4 mg every 5 minutes up to 3 doses. Patients should be advised to take 1 dose promptly in response to chest pain. If pain is unrelieved or worsened 3 to 5 minutes after 1 dose, the patient or caregiver should call 9-1-1 immediately (ACC/AHA [Amsterdam 2014]; ACCF/AHA [O'Gara 2013]). Topical 2% ointment: 1/2” upon rising and 1/2” 6 hours later; if necessary, the dose may be doubled to 1” and subsequently doubled again to 2” if response is inadequate. Doses of 1/2” to 2” were used in clinical trials. Recommended maximum: 2 doses/day; include a nitrate free-interval ~10 to 12 hours/day. Topical patch, transdermal: 0.2 to 0.4 m

(For additional information see "Nitroglycerin (glyceryl trinitrate): Pediatric drug information") Note: Nitronal IV solution has been discontinued in the US for more than 1 year. Sympathomimetic vasopressor extravasation injury (alternative to phentolamine) (off-label use; based on limited data): Topical 2% ointment: 4 mm/kg applied as a thin ribbon to site of ischemia; may repeat after 8 hours if needed (Wong 1992) or apply a 1-inch strip to site of ischemia; may repeat every 8 hours if needed (Denkler 1989; Reynolds 2014). Additional data may be necessary to further define the role of topical nitroglycerine in this condition.

Refer to adult dosing.

There are no dosage adjustments provided in the manufacturer's labeling.

Warnings & Precautions

Source: Lexicomp

Headache

Dose-related headaches may occur, especially during initial dosing.

Hypotension/bradycardia

Severe hypotension and shock may occur (even with small doses); paradoxical bradycardia and increased angina pectoris may accompany hypotension. Orthostatic hypotension may also occur; ethanol may accentuate this. Use with caution in volume depletion, preexisting hypotension, constrictive pericarditis, aortic or mitral stenosis, and extreme caution with inferior wall MI and suspected right ventricular involvement. According to the ACCF/AHA, avoid use in patients with severe hypotension (SBP • Increased intracranial pressure: Nitroglycerin may precipitate or aggravate increased intracranial pressure and subsequently may worsen clinical outcomes in patients with neurologic injury (eg, intracranial hemorrhage, traumatic brain injury) (Rangel-Castilla 2008). Some products are contraindicated in patients with increased intracranial pressure. Disease-related concerns:

Hypertrophic cardiomyopathy (HCM)

Avoid use in patients with HCM with outflow tract obstruction; nitrates may reduce preload, exacerbating obstruction and cause hypotension or syncope and/or worsening of heart failure (ACCF/AHA [Gersh, 2011]). Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Dosage form specific issues:

Intra-anal ointment

Use caution when treating rectal anal fissures with nitroglycerin in patients with suspected or known significant cardiovascular disorders (eg, cardiomyopathies, heart failure, acute MI); intra-anal nitroglycerin administration may decrease systolic blood pressure and decrease arterial vascular resistance.

Long-acting agents

Avoid use of long-acting agents in acute MI or acute HF; cannot easily reverse effects if adverse events develop.

Propylene glycol

Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP 1997; Zar 2007).

Transdermal patches

May contain conducting metal (eg, aluminum); remove patch prior to MRI. Other warnings/precautions:

Tolerance

May occur; cross tolerance to other nitro compounds have been reported. Appropriate dosing is needed to minimize tolerance development.

Pregnancy & Lactation

Pregnancy

FDA category B

Animal reproduction studies have not been conducted with all products; adverse events were not observed in animal reproduction studies conducted using the ointment. Nitroglycerin crosses the placenta (David 2000). Concentrations following application of a transdermal patch 0.4 mg/hour were low but detectable in the fetal serum (fetal/maternal ratio: 0.23) (Bustard 2003). Nitroglycerin may be used in pregnancy when immediate relaxation of the uterus is needed (ACOG 183 2017; Axemo 1998; Chandraharan 2005). Intravenous nitroglycerin may be used to treat pre-eclampsia with pulmonary edema (ESG 2011).

Lactation

It is not known if nitroglycerin is present in breast milk. According to the manufacturer, the decision to continue or discontinue breastfeeding during therapy should take into account the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. Information related to the use of nitroglycerin and breastfeeding is limited (Böttiger 2010; O’Sullivan 2011).

Monitoring

Clinical pearl	Blood pressure, heart rate; consult individual institutional policies and procedures

Chemistry & Properties

Formula	C3H5N3O9
Molecular weight	227.09 g/mol
IUPAC name	1,3-dinitrooxypropan-2-yl nitrate
CAS	55-63-0
PubChem CID	4510
InChIKey	`SNIOPGDIGTZGOP-UHFFFAOYSA-N`
logP	1.6 (XLogP 1.6)
Polar surface area	165.0 Å²
H-bond acceptors / donors	9 / 0

SMILES

C(C(CO[N+](=O)[O-])O[N+](=O)[O-])O[N+](=O)[O-]

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP2C19	Inhibitor	—
CYP2C19	Substrate	—
CYP2C8	Inhibitor	—
CYP2C9	Inhibitor	—
CYP3A4	Substrate	—

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Registered Products (5)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Nitroderm TTS-5	Patch 25 mg per 10 cm2	10 patch pack varies	Nabulsi Drug Store	2.590
Nitroderm TTS-10	Patch 50 mg per 20 cm2	10 patch	Nabulsi Drug Store	4.560
Deponit NT Transdermal	Patch 5 mg	10	Suleiman Tannous & Sons Co. Ltd	5.930
Nitroderm TTS-5	Patch 25 mg per 10 cm2	30 patch pack varies	Nabulsi Drug Store	7.310
Deponit NT Transdermal	Patch 10 mg	10	Suleiman Tannous & Sons Co. Ltd	8.950