Isosorbide Dinitrate

Pharmacologic Category

Antianginal Agent; Vasodilator

Dosing: Adult

Achalasia (off-label use): Sublingual: Immediate release: 5 mg administered 10 to 15 minutes before meals. Note: Clinical response is short acting and use does not provide complete relief of symptoms; consider risks before use (ACG [Vaezi 2013]).

Angina pectoris (prevention): Note: Due to slower onset of action, isosorbide dinitrate is not the drug of choice to abort an acute anginal episode. Tolerance to nitrate effects develops with chronic exposure; dose escalation does not overcome this effect. Tolerance can only be overcome by short periods of nitrate absence from the body. Nitrate-free intervals of ≥14 hours (immediate release products) or >18 hours (sustained release products) may help minimize tolerance.

Oral:

Immediate release: Initial: 5 to 20 mg 2 to 3 times daily; Maintenance: 10 to 40 mg 2 to 3 times daily or 5 to 80 mg 2 to 3 times daily (Anderson 2011)

Sustained release: 40 to 160 mg/day has been used in clinical trials (a nitrate free interval of >18 hours is recommended; however, a clinically efficacious dosage interval has not been clearly established) or 40 mg 1 to 2 times daily (Anderson 2011). Maximum dose: 160 mg/day (Dilatrate-SR only).

Sublingual [Canadian product]: 5 to 10 mg every 2 to 4 hours for prophylaxis of acute angina; may supplement with 5 to 10 mg prior to activities which may provoke an anginal episode.

Heart failure with reduced ejection fraction (off-label use): Note: As additional therapy for persistent NYHA class III or IV heart failure with reduced ejection fraction (HFrEF) despite optimal guideline directed medical therapies or for patients who cannot tolerate an ACE inhibitor, angiotensin II receptor blocker (ARB), or angiotensin II-neprilysin inhibitor (ARNI) (ACCF/AHA [Yancy 2013]; Colucci 2019).

Oral: Immediate release: Initial: 20 to 30 mg 3 or 4 times daily in combination with hydralazine 3 or 4 times daily; titrate dose every 2 to 4 weeks; maximum dose: 120 mg/day in divided doses (ACCF/AHA [Yancy 2013]). Some experts initiate 20 mg 3 times daily in combination with hydralazine 3 times daily; evaluate every 2 to 4 weeks and gradually titrate as tolerated to a target dose of 40 mg 3 times daily in combination with hydralazine 3 times daily (Colucci 2019; Meyer 2019). Note: May also consider use of the fixed-dose combination of isosorbide dinitrate/hydralazine instead of separate components (ACC/AHA/HFSA [Yancy 2017]; ACCF/AHA [Yancy 2013]).

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Elderly patients should be given lowest recommended adult daily doses initially and titrate upward. Refer to adult dosing.

Dosing: Renal Impairment: Adult

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

Hemodialysis: Supplemental dose is not necessary.

Peritoneal dialysis: Supplemental dose is not necessary.

Dosing: Hepatic Impairment: Adult

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

Use: Labeled Indications

Angina pectoris, prevention: Prevention of angina pectoris due to coronary artery disease.

Note: Due to slower onset of action, isosorbide dinitrate is not the drug of choice to abort an acute anginal episode.

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

AchalasiaLevel of Evidence [G]

Based on the American College of Gastroenterology (ACG) guidelines on the diagnosis and management of achalasia, isosorbide dinitrate may be considered for patients with achalasia who cannot use or refuse more definitive therapies (pneumatic dilation or surgical myotomy) and patients who have failed botulinum toxin injections.

Heart failure with reduced ejection fractionLevel of Evidence [A, G]

Data from a randomized, double-blind trial comparing enalapril and hydralazine plus isosorbide dinitrate in patients with chronic heart failure support the use of isosorbide dinitrate (in combination with hydralazine) in patients with intolerance to ACE inhibitor therapy ^Ref. Data from a randomized, double-blind, placebo-controlled trial in black patients with NYHA class III or IV heart failure on optimal guideline-directed medical therapy support the use of isosorbide dinitrate (in combination with hydralazine) for the management of this condition ^Ref.

Based on the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines for the management of heart failure, isosorbide dinitrate (in combination with hydralazine) is effective and recommended as additional therapy to optimal guideline-directed medical therapy for self-identified African-American patients with persistent NYHA class III or IV heart failure with reduced ejection fraction (HFrEF) or for patients who do not tolerate an ACE inhibitor or an angiotensin II receptor blocker (ARB) ^Ref. Some experts recommend isosorbide dinitrate (in combination with hydralazine) in addition to optimal guideline-directed medical therapy for black and nonblack patients with persistent NYHA class III or IV HFrEF, particularly for those with low output states or hypertension, or for patients who do not tolerate an ACE inhibitor, ARB, or angiotensin II-neprilysin inhibitor (ARNI) ^Ref.

Level of Evidence Definitions

Level of Evidence Scale

Class and Related Monographs

Nitrates

Clinical Practice Guidelines

Achalasia:

ACG, “2013 ACG Clinical Guideline for the Diagnosis and Management of Achalasia,” July 2013

Heart Failure:

ACC/AHA/HFSA “Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure,” August 2017

ACC/AHA/HFSA, “2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure,” May 2016

ACCF/AHA, “2013 ACCF/AHA Guideline for the Management of Heart Failure,” June 2013

Ischemic Heart Disease:

ACC/AHA/AATS/PCNA/SCAI/STS, "2014 Focused Update of the Guideline for the Diagnosis and Management of Patients with Stable Ischemic Heart Disease," July 2014

ACCF/AHA/ACP/AATS/PCNA/SCAI/STS, “2012 Guideline for the Diagnosis and Management of Patients with Stable Ischemic Heart Disease,” November 2012

Administration: Oral

Do not administer around the clock; allow nitrate-free interval ≥14 hours (immediate release products) and >18 hours (sustained release products). Do not chew or crush sublingual tablets or sustained release formulations.

Immediate release products: For twice daily dosing, consider administering at 8 AM and 1 PM. For 3 times daily dosing, consider 8 AM, 1 PM, and 6 PM.

Sustained release products: Consider once daily in morning or twice-daily dosing at 8 AM and between 1 PM and 2 PM.

Storage/Stability

Extended-release tablets: Store at 20°C to 25°C (68°F to 77°F).

Sustained-release capsules and immediate-release tablets: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light.

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to prevent chest pain.

• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Headache

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Severe dizziness

• Passing out

• Slow heartbeat

• Fast heartbeat

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Safety Issues

Sound-alike/look-alike issues:

Contraindications

Hypersensitivity to isosorbide dinitrate or any component of the formulation; concurrent use with phosphodiesterase inhibitors (sildenafil, tadalafil, vardenafil, or avanafil); concurrent use with riociguat

Canadian labeling: Additional contraindications (not in US labeling): Cardiogenic shock or risk of cardiogenic shock developing

Warnings/Precautions

Concerns related to adverse effects:

• Hypotension/bradycardia: Severe hypotension can occur; paradoxical bradycardia and increased angina pectoris can accompany hypotension. Orthostatic hypotension can also occur; ethanol can accentuate this. Use with caution in volume depletion and hypotension, and use with extreme caution with inferior wall MI and suspected right ventricular infarctions. Severe hypotension, particularly with upright posture, may occur with even small doses.

• Intracranial pressure increased: Nitrates 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).

Disease-related concerns:

• Cardiovascular disease: Not recommended in patients with acute MI or HF (cannot easily reverse effects if adverse events develop).

• 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.

Other warnings/precautions:

• Tolerance: Appropriate dosing intervals are needed to minimize tolerance development. Tolerance can only be overcome by short periods of nitrate absence from the body. Dose escalation does not overcome this effect. When used for HF in combination with hydralazine, tolerance is less of a concern (Gogia 1995).

* See Cautions in AHFS Essentials for additional information.

Geriatric Considerations

The first dose of nitrates (sublingual, chewable, oral) should be taken in a physician's office to observe for maximal cardiovascular dynamic effects and adverse effects (eg, orthostatic blood pressure drop, headache). The use of nitrates for angina may occasionally promote reflux esophagitis. This may require dose adjustments or changing therapeutic agents to correct this adverse effect.

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. Nitric oxide donors, such as isosorbide, have been evaluated for pre-eclampsia and cervical ripening; isosorbide dinitrate use in these conditions is not currently recommended (Kalidindi 2012; Ramirez 2011).

Breast-Feeding Considerations

It is not known if isosorbide dinitrate is present in breast milk. The manufacturer recommends that caution be exercised when administering isosorbide dinitrate to breastfeeding women.

Briggs' Drugs in Pregnancy & Lactation

• Isosorbide Dinitrate

Adverse Reactions

Frequency not defined.

Cardiovascular: Hypotension, rebound hypertension, syncope, unstable angina pectoris

Central nervous system: Headache

* See Cautions in AHFS Essentials for additional information.

Allergy and Idiosyncratic Reactions

• Nitrate Allergy

Metabolism/Transport Effects

Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions Open Interactions

Alcohol (Ethyl): May enhance the vasodilatory effect of Vasodilators (Organic Nitrates). Risk C: Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Risk D: Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Bromperidol: Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents. Risk X: Avoid combination

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Risk D: Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Risk D: Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Risk D: Consider therapy modification

Dapoxetine: May enhance the orthostatic hypotensive effect of Vasodilators (Organic Nitrates). Risk C: Monitor therapy

Dapsone (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Risk C: Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Risk D: Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Risk C: Monitor therapy

Local Anesthetics: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Local Anesthetics. Specifically, the risk for methemoglobinemia may be increased. Risk C: Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Risk D: Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Risk D: Consider therapy modification

Molsidomine: May enhance the hypotensive effect of Vasodilators (Organic Nitrates). Risk C: Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nitric Oxide: May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Risk D: Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the vasodilatory effect of Vasodilators (Organic Nitrates). Risk X: Avoid combination

Prilocaine: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine in infants receiving such agents. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Rilmenidine: Vasodilators (Organic Nitrates) may enhance the hypotensive effect of Rilmenidine. Risk C: Monitor therapy

Riociguat: Vasodilators (Organic Nitrates) may enhance the hypotensive effect of Riociguat. Risk X: Avoid combination

Rosiglitazone: Vasodilators (Organic Nitrates) may enhance the adverse/toxic effect of Rosiglitazone. Specifically, a greater risk of ischemia and other adverse effects has been associated with this combination in some pooled analyses. Risk C: Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Sodium Nitrite: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Risk D: Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Genes of Interest

• Cytochrome P450 3A4

Monitoring Parameters

Blood pressure, heart rate

Advanced Practitioners Physical Assessment/Monitoring

Assess patient closely for volume depletion, hypotension, and right ventricular infarction. Tolerance to nitrates develops and appropriate dosing intervals are needed to minimize tolerance. Teach patient importance of maintaining dosing schedule.

Nursing Physical Assessment/Monitoring

Assess blood pressure and monitor for hypotension and tolerance at regular intervals during therapy. Teach patient importance of maintaining dosing schedule to provide drug-free period.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule Extended Release, Oral:

Dilatrate-SR: 40 mg [contains fd&c yellow #10 (quinoline yellow)]

Tablet, Oral:

Isordil Titradose: 5 mg [scored; contains fd&c red #40]

Isordil Titradose: 40 mg [scored; contains brilliant blue fcf (fd&c blue #1), fd&c yellow #10 (quinoline yellow), fd&c yellow #6 (sunset yellow)]

Generic: 5 mg, 10 mg, 20 mg, 30 mg, 40 mg

Tablet Extended Release, Oral:

Generic: 40 mg [DSC]

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Generic: 10 mg, 30 mg

Tablet Sublingual, Sublingual:

Generic: 5 mg

Anatomic Therapeutic Chemical (ATC) Classification

• C01DA08
• C05AE02

Generic Available (US)

May be product dependent

Pricing: US

Capsule, controlled release (Dilatrate-SR Oral)

40 mg (per each): $5.59

Tablets (Isordil Titradose Oral)

5 mg (per each): $11.00

40 mg (per each): $24.22

Tablets (Isosorbide Dinitrate Oral)

5 mg (per each): $0.99

10 mg (per each): $0.73 - $1.08

20 mg (per each): $0.86 - $1.19

30 mg (per each): $1.31

40 mg (per each): $20.54

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

Isosorbide dinitrate and other nitrates form free radical nitric oxide. In smooth muscle, nitric oxide activates guanylate cyclase which increases guanosine 3’5’ monophosphate (cGMP) leading to dephosphorylation of myosin light chains and smooth muscle relaxation. Produces a vasodilator effect on the peripheral veins and arteries with more prominent effects on the veins. Primarily reduces cardiac oxygen demand by decreasing preload (left ventricular end-diastolic pressure); may modestly reduce afterload. Additionally, coronary artery dilation improves collateral flow to ischemic regions.

Pharmacodynamics/Kinetics

Onset of action: Sublingual tablet: ~2 to 5 minutes; Oral tablet and capsule (includes extended-release formulations): ~1 hour

Duration: Sublingual tablet: 1 to 2 hours; Oral tablet and capsule (includes extended-release formulations): Up to 8 hours

Distribution: V_d: 2 to 4 L/kg

Metabolism: Extensively hepatic to conjugated active metabolites isosorbide 5-mononitrate and 2-mononitrate

Bioavailability: Highly variable (10% to 90%); increases with chronic therapy

Half-life elimination: Parent drug: ~1 hour; Metabolites (5-mononitrate: 5 hours; 2-mononitrate: 2 hours)

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia and changes in salivation (normal salivary flow resumes upon discontinuation).

Effects on Bleeding

No information available to require special precautions

Related Information

• Nitrates
• Oral Medications That Should Not Be Crushed or Altered

Index Terms

ISD; ISDN

References

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Antman EM, Anbe SC, Alpert JS, et al, “ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction - Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction),” Circulation, 2004, 110(5):588-636. Available at http://www.circulationaha.org/cgi/content/full/110/5/588[PubMed 15289388]

Cheitlin MD, Hutter AM Jr, Brindis RG, et al, “ACC/AHA Expert Consensus Document. Use of Sildenafil (Viagra) in Patients With Cardiovascular Disease. American College of Cardiology/American Heart Association,” J Am Coll Cardiol, 1999, 33(1):273-82.[PubMed 9935041]

Cohn JN, Archibald DG, Ziesche S, et al, "Effect of Vasodilator Therapy on Mortality in Chronic Congestive Heart Failure. Results of a Veterans Administration Cooperative Study," N Engl J Med, 1986, 314(24):1547-52.[PubMed 3520315]

Cohn JN, Johnson G, Ziesche S, et al, "A Comparison of Enalapril With Hydralazine-Isosorbide Dinitrate in the Treatment of Chronic Congestive Heart Failure," N Engl J Med, 1991, 325(5):303-10.[PubMed 2057035]

Colucci WS. Secondary pharmacologic therapy in heart failure withreduced ejection fraction (HFrEF) in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed November 8, 2019.

Dilatrate-SR (isosorbide dinitrate sustained-release capsules) [prescribing information]. Chesterbrook, PA: Auxilium Pharmaceuticals; October 2014.

Fihn SD, Gardin JM, Abrams J, et al, “2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons,” Circulation, 2012, 126(25):3097-137.[PubMed 23166211]

Gersh BJ, Maron BJ, Bonow RO, et al, “2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines,” Circulation, 2011, 124(24):e783-831.[PubMed 22068434]

Gogia H, Mehra A, Parikh S, et al, “Prevention of Tolerance to Hemodynamic Effects of Nitrates With Concomitant Use of Hydralazine in Patients With Chronic Heart Failure,” J Am Coll Cardiol, 1995, 26(7):1575-80.[PubMed 7594088]

ISDN (isosorbide dinitrate) [product monograph]. Vaughan, Ontario, Canada: AA Pharma Inc; June 2010.

IsoDitrate (isosorbide dinitrate) extended-release tablets [prescribing information]. Middlesex, NJ: Corepharma: April 2010.

Isordil Titradose (isosorbide dinitrate) tablets [prescribing information]. Bridgewater, NJ: Valeant Pharmaceuticals; August 2019.

Kalidindi M, Velauthar L, Khan K, et al, "The Role of Nitrates in the Prevention of Preeclampsia: An Update," Curr Opin Obstet Gynecol, 2012, 24(6):361-7.[PubMed 23108288]

Lindenfeld J, Albert NM, Boehmer JP, et al, “HFSA 2010 Comprehensive Heart Failure Practice Guideline,” J Card Fail, 2010, 16(6):e1-194.[PubMed 20610207]

Meyer TE. Initial pharmacologic therapy of heart failure with reduced ejection fraction in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed October 24, 2019.

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Brand Names: International

Angibid SR (KR); Angitrit (SG); Angsobide (MY); Cardil (PY); Cardonit (HU); Cardopax (DK); Carsodil (KR); Carvasin (IT); Cedocard (AE, AT, BE, CY, GB, ID, IE, LU, NL, TR); Cedocard Retard (AT, ID, NL); Coronex (NZ); Diconpin (DE); Dicor (UA); Dilatrate-SR (BM); Flindix (PT); Gasrobid (ID); Hartsorb (TH); Huma-Sorbide (HU); Imtack (IE); ISDN (DE); ISDN AL (HU); ISDN-Q (HU); ISDN-ratiopharm (LU); Iso Mack (CH, HU); Iso Mack Retard (AE, BH, CY, IQ, IR, JO, KW, LY, OM, QA, SA, SY, YE); Iso-Lacer (ES); Iso-Puren (DE); Isobide (TW); Isobinate (TH); Isocard (LU); Isocard Retard (AE, BH, CY, IQ, IR, JO, KW, LY, OM, SA, SY, YE); Isocord (CO); Isoday 40 (AE, BH, CY, IQ, IR, JO, KW, LY, OM, QA, SA, SY, YE); Isodex (LB); Isodinit (LU, RO); Isoket (AE, AR, BG, CH, CN, CY, CZ, DE, EE, HU, ID, IE, IL, JO, KW, LB, LT, LU, LV, MT, MY, PH, PL, PY, RU, SA, SG, TR, UA, UY, VE, VN); Isoket Retard (AE, CH, CZ, DE, EG, GB, IN, KR, KW); Isoket Spray (KR); Isomack (AT, HU, LU, VN); Isomack Spray (KR); Isorbid (MX); Isorbide (PE); Isordil (AE, AR, AU, BH, BR, CY, HN, ID, IL, IN, IQ, IR, JO, KW, LB, LU, LY, NL, OM, PH, PK, PY, SA, SY, TR, YE, ZA); Isorem (MT, TR); Isotonax (LU); Langoran (FR); Langoran LP (FR); Maycor (DE); Nitrol R (JP); Nitrosid (FI); Nitrosid Retard (FI); Nitrosorbide (BF, BJ, CI, ET, GH, GM, GN, IT, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZM, ZW); Nitrosorbon (DE, PH); Pensodril (GR); Risordan (FR, GR); Risordan LP (FR); Soni-Slo (AE, BF, BH, BJ, CI, CY, ET, GH, GM, GN, IE, IQ, IR, JO, KE, KW, LR, LY, MA, ML, MR, MU, MW, NE, NG, OM, QA, SA, SC, SD, SL, SN, SY, TN, TZ, UG, YE, ZM, ZW); Sorbangil (NO, SE); Sorbid (BD); Sorbidilat (CH); Sorbidin (AU, VN); Sorbitrate (IN, LU); Sorbonit (HN, HU, PL); TD Spray Iso Mack (HU, LU); Tinidil (HR); Vascarbine (BD); Vascardin (AE, BB, BF, BH, BJ, BM, BS, BZ, CI, CY, ET, GH, GM, GN, GY, ID, IQ, IR, JM, JO, KE, KW, LR, LY, MA, ML, MR, MU, MW, NE, NG, OM, QA, SA, SC, SD, SL, SN, SR, SY, TN, TT, TZ, UG, YE, ZM, ZW); Vasot (BD)

Last Updated 2/26/20