Sodium Nitroprusside (nitroprusside sodium)

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Sodium nitroprusside is administered by IV infusion only using a controlled-infusion device (i.e., infusion pump); IV infusion devices regulated only by gravity or mechanical clamps should not be used. The rate of administration should be adjusted to maintain the desired hypotensive effect, as determined by continuous monitoring of blood pressure, using either a continually reinflated sphygmomanometer or, preferably, an intra-arterial pressure sensor. The drug should be administered for no longer than 10 minutes at the maximum infusion rate (i.e., 10 mcg/kg per minute). When titrating sodium nitroprusside infusion, blood pressure should be assessed for at least 5 minutes before further titrating the infusion rate.

Sodium nitroprusside is commercially available prediluted in 0.9% sodium chloride injection (0.5 mg/mL and 0.2 mg/mL concentrations) and as an injection concentrate (25 mg/mL). Commercially available sodium nitroprusside injection concentrate (25 mg/mL) must be further diluted prior to IV infusion. The contents of one vial of injection concentrate containing 50 mg of the drug should be diluted in 250-1000 mL of 5% dextrose injection. Vials of the drug are for single use only. Nitroprusside solutions prepared using the injection concentrate should be protected from light by promptly wrapping the containers in the supplied opaque sleeve, aluminum foil, or other opaque material; it is not necessary to cover the infusion drip chamber or IV tubing. If properly protected from light, diluted solutions of the drug are stable for 24 hours. The infusion solution has a clear colorless to red/brown color; if it is blue, green, or bright red, it should not be used. No other drug should be added to the infusion fluid for simultaneous administration with sodium nitroprusside.

Sodium nitroprusside vials should be stored protected from light in their carton until use at 20-25degreesC.

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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)

There are no severe interactions for this drug.

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

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)

Selected Antihypertensives/Tizanidine

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

MECHANISM OF ACTION: Tizanidine is an alpha-2 agonist. Concurrent use with antihypertensive agents may result in additive effects on blood pressure.(1)

CLINICAL EFFECTS: Concurrent use of antihypertensives and tizanidine may result in hypotension.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. The risk of hypotension may be decreased by careful titration of tizanidine dosages and monitoring for hypotension prior to dose advancement. Counsel patients about the risk of orthostatic hypotension.(1)

DISCUSSION: Severe hypotension has been reported following the addition of tizanidine to existing lisinopril therapy.(2-4)

*Sodium nitroprusside should not be used in the treatment of compensatory hypertension (e.g., arteriovenous shunt, coarctation of the aorta).

*The use of sodium nitroprusside to produce controlled hypotension during surgery is contraindicated in patients with inadequate cerebral circulation and is not intended for use during emergency surgery in patients near death (American Society of Anesthesiologists (ASA) class 5E).

*Use of the drug is contraindicated in patients with congenital (Leber's) optic atrophy or tobacco amblyopia; these conditions, although rare, are associated with absent or deficient thiosulfate sulfurtransferase (rhodanase), and these patients have unusually high cyanogen to thiocyanate ratios.

*Sodium nitroprusside is contraindicated in patients with acute heart failure associated with reduced peripheral vascular resistance, such as high-output heart failure that may accompany endotoxic sepsis.

*Concomitant use of sodium nitroprusside and phosphodiesterase (PDE) type 5 inhibitors (e.g., sildenafil, tadalafil, vardenafil) or soluble guanylate cyclase stimulators (e.g., riociguat) is contraindicated.

• Coarctation of aorta

• Chronic obstructive pulmonary disease
• Intracerebral hemorrhage
• Intracranial hypertension
• Leber's hereditary optic atrophy
• Severe renal impairment
• Tobacco amblyopia
• Vitamin b12 deficiency

• Anemia
• Disease of liver
• Hyponatremia
• Hypothyroidism
• Hypovolemia

Adverse effects resulting from IV administration of sodium nitroprusside are uncommon and are usually associated with a too-rapid reduction in blood pressure. Excessive hypotension and cyanide toxicity are the most common.

Less Frequent

• Cyanide toxicity
• Methemoglobinemia
• Severe hypotension

Rare or Very Rare

• Abnormal ECG
• Bradycardia
• Hypothyroidism
• Ileus
• Intracranial hypertension
• Platelet aggregation inhibition
• Tachycardia

Rare or Very Rare

• Acute abdominal pain
• Dizziness
• Flushing
• Headache disorder
• Hyperhidrosis
• Injection site sequelae
• Muscle fasciculation
• Nausea
• Palpitations
• Skin rash

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Efficacy of sodium nitroprusside in pediatric patients has been established based on adult trials and supported by 2 studies in pediatric patients: a parallel, dose-ranging study and a long-term infusion study in which sodium nitroprusside dosage was titrated according to blood pressure. The primary efficacy variable in these studies was mean arterial pressure (MAP). The patients were <17 years of age; at least 50% of the patients were prepubertal, and about 50% of prepubertal patients were <2 years of age, including 4 neonates. Both studies demonstrated the blood pressure-lowering effect of sodium nitroprusside. In the latter study, sodium nitroprusside reduced MAP below that of placebo control for at least 12 hours. Similar effects on MAP were observed in all age groups in these studies, and no novel safety issues were noted.

Based on animal findings and its mechanism of action, sodium nitroprusside may lead to cyanide exposure and adverse effects on the fetus. Available postmarketing data in pregnant women are insufficient to establish a drug-associated risk of adverse pregnancy outcomes with sodium nitroprusside. Studies in pregnant sheep have shown that sodium nitroprusside crosses the placenta and effects were dose-related.

Prolonged use and higher dosages of sodium nitroprusside during pregnancy can result in cyanide toxicity, which may be fatal to a developing fetus. In the unusual situation that there is no alternative therapy to sodium nitroprusside, pregnant women should be informed of the potential fetal risk.

There are no data on the presence of sodium nitroprusside in human milk, the effects on the breast-fed infant, or the effects on milk production; however, thiocyanate, a metabolite of sodium nitroprusside, is present in human milk. It is unclear if and for how long thiocyanate levels in milk are clinically relevant.

The manufacturer states that special caution should be used with sodium nitroprusside in geriatric patients, as they may be more sensitive to the hypotensive effects of the drug.

Geriatric patients may be more sensitive to the hypotensive effects of sodium nitroprusside, therefore caution should be exerted with use in this patient population.