Nitroglycerin (nitroglycerin)

Dosage of nitroglycerin must be carefully adjusted according to the patient's requirements and response and the smallest effective dosage should be used. When nitroglycerin is administered IV, the type of IV administration set used, polyvinyl chloride (PVC) or non-PVC, must be considered in dosage estimations. It should be noted that dosages commonly used in early published studies were based on the use of PVC administration sets and are too high when non-PVC administration sets are used.

Continuous monitoring of blood pressure and heart rate, as well as other appropriate parameters (e.g., pulmonary capillary wedge pressure), must be performed in all patients. Adequate systemic blood pressure and coronary perfusion pressure must be maintained. Some patients with normal or low left ventricular filling pressures or pulmonary capillary wedge pressure may be extremely sensitive to the effects of IV nitroglycerin and may respond fully to dosages as low as 5 mcg/minute; these patients require particularly careful monitoring and dosage titration.

Nitroglycerin is administered lingually, sublingually, topically, or by IV infusion.

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Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Nitrates & Nitric Oxide Donors/Riociguat

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Nitrates activate guanyl cyclase, an enzyme that increases levels of cyclic guanosine monophosphate (cGMP), which produces smooth muscle relaxation. Riociguat stimulates the nitric oxide-soluble guanylate cyclase-cGMP pathway and also increases cGMP. Concurrent use of nitrates with riociguat results in potentiation of the effect of both agents.(1)

CLINICAL EFFECTS: The concurrent use riociguat and nitrates potentiates the hypotensive effects of both agents, which may result in dizziness, syncope, heart attack, or stroke.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The administration of riociguat to patients receiving nitrates, or nitric oxide donors, in any form is contraindicated.(1)

DISCUSSION: Riociguat (2.5 mg) potentiated the blood pressure lowering effect of sublingual nitroglycerin (0.4 mg) when taken 4 hour and 8 hours after riociguat. Syncope was reported in some patients.(1)

Nitrates/Cgmp Specific Pde Type-5 Inhibitors

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Nitrates activate guanyl cyclase, an enzyme that increases levels of cyclic guanosine monophosphate (cGMP). cGMP produces smooth muscle relaxation. Avanafil,(1) sildenafil,(2) tadalafil,(3,4) and vardenafil (5-7) inhibit phosphodiesterase type 5 (PDE5), which is responsible for the breakdown of cGMP. Concurrent use of nitrates with avanafil,(1) sildenafil,(2) tadalafil,(3,4) or vardenafil(5-7) results in potentiation of the effect of nitrates.

CLINICAL EFFECTS: The concurrent use of CGMP specific PDE type-5 inhibitors and nitrates potentiates the hypotensive effects of nitrates(1-7) which may result in dizziness, syncope, heart attack, or stroke.(4) The concurrent use of sildenafil and sodium nitroprusside may potentiate the antiaggregatory effect of sodium nitroprusside in addition to increased hypotensive effects.(2)

PREDISPOSING FACTORS: Plasma levels of the PDE type-5 inhibitor may be higher in the following patients: those older than 65, with hepatic impairment, with severe renal impairment, or using concomitant CYP3A4 inhibitors. This may increase the severity of the interaction.

PATIENT MANAGEMENT: The administration of avanafil to patients receiving organic nitrates, either regularly and/or intermittently, is contraindicated. In a patient who has taken avanafil, at least 12 hours should elapse after the last dose of avanafil before nitrate administration is considered and it should only be administered under close medical supervision with appropriate hemodynamic monitoring.(1) The administration of sildenafil to patients receiving organic nitrates, either regularly and/or intermittently, in any form is contraindicated.(2) The administration of tadalafil to patients receiving any form of organic nitrate, either regularly and/or intermittently, is contraindicated.(3,4) Patients should be instructed to seek immediate medical attention if they experience anginal chest pain following tadalafil. In such cases where nitrate administration is considered medically necessary, at least 48 hours should elapse after tadalafil administration before nitrate administration is considered. In such cases, nitrates should only be administered under close medical supervision with appropriate hemodynamic monitoring.(4) The administration of vardenafil to patients receiving nitrates or nitric oxide donors is contraindicated.(5-7) In patients prescribed vardenafil in whom nitrate administration is deemed medically necessary in a life-threatening situation, the Canadian manufacturer of vardenafil states that at least 24 hours should have elapsed after the last dose of vardenafil before the nitrate administration is considered. Nitrates should only be administered under close medical supervision with appropriate hemodynamic monitoring.(7) The concomitant use of nicorandil(8) or subinguinal nitroglycerin(9) and PDE type-5 inhibitors is contraindicated. Treat hypotension resulting from concurrent use as a nitrate overdose, with elevation of the extremities and central volume expansion.(10)

DISCUSSION: Nitrates activate guanylate cyclase, an enzyme that increases levels of cGMP. cGMP produces smooth muscle relaxation. Avanafil,(1) sildenafil,(2) tadalafil,(3,4) and vardenafil (5-7) inhibit PDE5, which is responsible for the breakdown of cGMP. Concurrent use of nitrates with avanafil,(1) sildenafil,(2) tadalafil,(3,4) or vardenafil(5-7) results in potentiation of the effect of nitrates. It is unknown when nitrates, if necessary, can be safely administered to patients who have taken CGMP specific PDE type-5 inhibitors. Following a single 100 mg oral dose of sildenafil, peak plasma levels are approximately 440 ng/mL and levels 24 hours post dose are approximately 2 ng/ml. Sildenafil plasma levels at 24 hours post dose are three to eight times higher in the following patients: those age greater than 65, those with hepatic impairment, those with severe renal impairment (creatinine clearance less than 30 ml/min), and those with concomitant use of potent CYP P-450-3A4 inhibitors (erythromycin). Although plasma levels of sildenafil are lower at 24 hours post dose, the manufacturer of sildenafil states that it is still unknown whether nitrates can safely be coadministered at that time.(2) In vitro studies with human platelets have shown that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside.(2) In a study of 150 subjects who received tadalafil (20 mg) daily for 7 days, sublingual nitroglycerin was administered at 2, 4, 8, 24, 48, 72, and 96 hours after tadalafil. A significant interaction between tadalafil and nitroglycerin was observed up to and including 24 hours post-tadalafil. At 48 hours, the interaction was not observed by most hemodynamic measures. After 48 hours, the interaction was not detectable.(4) In a population-based cohort study of 61,487 men who received nitrates, 5,710 (9%) concurrently received PDE Type-5 inhibitors (PDE5i). Crude hazard ratios found a significant and inverse association between combination use of nitrates and PDE5i and all cause, cardiovascular, and non-cardiovascular mortality. All-cause mortality incidence rates were 2.69 cases per 100 person-years for the nitrate and PDE5i group vs 3.83 cases per 100 person-years in the nitrate-only group. Concurrent use of nitrates and PDE5i found a multivariate adjusted HR for all-cause mortality of 1.39 (95% CI: 1.28-1.51). Concurrent use of nitrates and PDE5i found an adjusted HR for cardiovascular death, non-cardiovascular death, myocardial infarction, heart failure, revascularization, and major adverse cardiovascular event (MACE) in patients treated with both nitrates and PDE5i was 1.34 (95% CI: 1.11-1.62), 1.40 (95% CI: 1.27-1.54), 1.72 (95% CI: 1.55-1.90), 1.67 (95% CI: 1.48-1.90), 1.95 (95% CI: 1.78-2.13), and 1.70 (95% CI: 1.58-1.83), respectively, compared with patients with nitrates only.(11)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Nitrates/Ergot Alkaloids

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Decreased first-pass metabolism of ergot alkaloids. Ergot alkaloids may precipitate angina pectoris.

CLINICAL EFFECTS: Increased standing systolic blood pressure and angina attacks may occur.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid administration of ergot alkaloids to patients receiving nitroglycerin for angina. When it is necessary to give this combination, monitor the patient for increased effects of the ergot alkaloid. Reduce the dose of ergot alkaloid as necessary.

DISCUSSION: Dihydroergotamine has been reported to precipitate angina pectoris. Nitroglycerin administration to patients receiving dihydroergotamine increased the plasma dihydroergotamine level and area under the plasma concentration-time curve. An increase in the mean standing systolic blood pressure was measured.

Nitroglycerin/Alteplase

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Nitroglycerin may increase hepatic blood flow, enhancing the hepatic metabolism of alteplase (t-PA).

CLINICAL EFFECTS: The thrombolytic effect of alteplase may be decreased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, avoid coadministration of alteplase and nitroglycerin. If both drugs must be given concomitantly use caution when administering these agents. Be aware that the therapeutic effects of alteplase may be impaired.

DISCUSSION: In a study, nitroglycerin administration decreased plasma levels of alteplase reducing the thrombolytic effects. In a non-randomized study involving patients with suspected infarction, stable coronary artery reperfusion occurred in 91% of the patients receiving alteplase plus saline solution compared to 44% receiving alteplase plus intravenous nitroglycerin. Patients receiving alteplase and nitroglycerin concomitantly had lower mean plasma t-PA antigen concentrations than patients receiving alteplase alone. The differences persisted for more than 6 hours after completing the alteplase infusion.(1) In an earlier subset of the above study, patients with acute myocardial infarctions who received alteplase alone demonstrated an earlier peak serum creatine kinase and showed signs of reperfusion more frequently and sooner than did patients receiving alteplase plus nitroglycerin. In addition, patients receiving alteplase and nitroglycerin had a greater incidence of in-hospital adverse events and a higher incidence of reocclusion.(2)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Nitroglycerin (Sublingual)/Apomorphine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Apomorphine causes dose-dependent decreases in blood pressure. Concurrent use with sublingual nitroglycerin may result in additive effects on blood pressure.(1)

CLINICAL EFFECTS: Concurrent use of sublingual nitroglycerin and apomorphine may result in orthostatic hypotension with or without dizziness, nausea, or syncope.(1)

PREDISPOSING FACTORS: The risk of orthostatic hypotension may be increased during dose escalation of apomorphine and in patients with renal or hepatic impairment.(1)

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. Advise the patient to lie down before and for 45 minutes after taking nitroglycerin. Counsel patients about the risk of orthostatic hypotension.(1)

DISCUSSION: Healthy volunteers who took sublingual nitroglycerin (0.4 mg) concomitantly with apomorphine experienced a mean largest decrease in supine systolic blood pressure (SBP) of 9.7 mm Hg and in supine diastolic blood pressure (DBP) of 9.3 mm Hg, and a mean largest decrease in standing SBP and DBP of 14.3 mm Hg and 13.5 mm Hg, respectively. The maximum decrease in SBP and DBP was 65 mm Hg and 43 mm Hg, respectively. When apomorphine was taken alone, the mean largest decrease in supine SBP and DBP was 6.1 mm Hg and 7.3 mm Hg, respectively, and in standing SBP and DBP was 6.7 mm Hg and 8.4 mm Hg, respectively.(1)

Selected Antihypertensives And Vasodilators/Apomorphine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Apomorphine causes dose-dependent decreases in blood pressure. Concurrent use with antihypertensive agents may result in additive effects on blood pressure.(1)

CLINICAL EFFECTS: Concurrent use of antihypertensives and apomorphine may result in orthostatic hypotension with or without dizziness, nausea, or syncope.(1)

PREDISPOSING FACTORS: The risk of orthostatic hypotension may be increased during dose escalation of apomorphine and in patients with renal or hepatic impairment.(1)

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. Counsel patients about the risk of orthostatic hypotension.(1)

DISCUSSION: Healthy volunteers who took sublingual nitroglycerin (0.4 mg) concomitantly with apomorphine experienced a mean largest decrease in supine systolic blood pressure (SBP) of 9.7 mm Hg and in supine diastolic blood pressure (DBP) of 9.3 mm Hg, and a mean largest decrease in standing SBP and DBP of 14.3 mm Hg and 13.5 mm Hg, respectively. The maximum decrease in SBP and DBP was 65 mm Hg and 43 mm Hg, respectively. When apomorphine was taken alone, the mean largest decrease in supine SBP and DBP was 6.1 mm Hg and 7.3 mm Hg, respectively, and in standing SBP and DBP was 6.7 mm Hg and 8.4 mm Hg, respectively.(1)

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• Constrictive pericarditis
• Intracranial hypertension
• Pericardial tamponade
• Restrictive cardiomyopathy

• Aortic valve stenosis
• Hypotension
• Intracerebral hemorrhage
• Intracranial hypertension
• Methemoglobinemia
• Mitral stenosis
• Severe anemia
• Severe hypoxemia

• Hypertrophic cardiomyopathy
• Hypotension
• Severe chronic heart failure

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More Frequent

• Syncope

Rare or Very Rare

• Allergic dermatitis
• Anaphylaxis
• Blurred vision
• Exfoliative dermatitis
• Hypoxia
• Methemoglobinemia
• Severe headache disorder
• Stevens-johnson syndrome
• Xerostomia

More Frequent

• Dizziness
• Flushing
• Headache disorder
• Hypotension
• Nervousness
• Orthostatic hypotension
• Paresthesia

Less Frequent

• Nausea
• Palpitations
• Tachycardia
• Vomiting

Rare or Very Rare

• Accidental fall
• Drowsy
• Dyspnea
• Fatigue
• General weakness
• Hyperhidrosis
• Pallor
• Skin rash
• Vertigo

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