Nitroprusside

Dosage Forms

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

Solution, Intravenous, as sodium:

Nipride RTU: 20 mg/100 mL in NaCl 0.9% (100 mL)

Nitropress: 25 mg/mL (2 mL)

Generic: 25 mg/mL (2 mL)

Solution, Intravenous, as sodium [preservative free]:

Nipride RTU: 10 mg/50 mL in NaCl 0.9% (50 mL [DSC]); 50 mg/100 mL in NaCl 0.9% (100 mL)

Generic: 25 mg/mL (2 mL)

Pharmacology

Mechanism of Action

Causes peripheral vasodilation by direct action on venous and arteriolar smooth muscle, thus reducing peripheral resistance; will increase cardiac output by decreasing afterload; reduces aortal and left ventricular impedance

Pharmacokinetics/Pharmacodynamics

Metabolism

Nitroprusside combines with hemoglobin to produce cyanide and cyanmethemoglobin. Cyanide detoxification occurs via rhodanase-mediated conversion of cyanide to thiocyanate; rhodanase couples cyanide molecules to sulfane sulfur groups from a sulfur donor (eg, thiosulfate, cystine, cysteine). This process has limited capacity and may become overwhelmed with large exposures once sulfur donor supplies are exhausted resulting in toxicity.

Excretion

Urine (as thiocyanate)

Onset of Action

Hypotensive effect: <2 minutes

Duration of Action

Hypotensive effect: 1-10 minutes

Half-Life Elimination

Nitroprusside, circulatory: ~2 minutes; Thiocyanate, elimination: ~3 days (may be doubled or tripled in renal failure)

Use: Labeled Indications

Acute decompensated heart failure (HF): Management of acute decompensated HF

Acute hypertension: Management of hypertensive crises; used for controlled hypotension to reduce bleeding during surgery

Use: Off Label

Hypertension during acute ischemic strokeyes

Based on the American Heart Association/American Stroke Association (AHA/ASA) Guidelines for the Early Management of Patients with Acute Ischemic Stroke, nitroprusside given in the management of hypertension during acute ischemic stroke is listed as an alternative approach to patients with this condition.

Contraindications

Treatment of compensatory hypertension (aortic coarctation, arteriovenous shunting); to produce controlled hypotension during surgery in patients with known inadequate cerebral circulation or in moribund patients (A.S.A. Class 5E) requiring emergency surgery; acute heart failure associated with reduced systemic vascular resistance (eg, septic shock); congenital (Leber's) optic atrophy or tobacco amblyopia; concomitant use with sildenafil, tadalafil, vardenafil, or riociguat

Canadian labeling: Additional contraindication (not in US labeling): Hypersensitivity to nitroprusside or any component of the formulation; uncorrected anemia or hypovolemia; hepatic disease; severe renal disease; disease states associated with vitamin B₁₂ deficiency

Dosage and Administration

Dosing: Adult

Acute hypertension: Initial: 0.3 to 0.5 mcg/kg/minute; may be titrated by 0.5 mcg/kg/minute every few minutes to achieve desired hemodynamic effect (Rhoney 2009); maximum dose: 10 mcg/kg/minute (for a maximum of 10 minutes). To avoid toxicity, some recommend a maximum dose of 2 mcg/kg/minute (Marik 2007).

Acute decompensated heart failure: IV: Initial: 5 to 10 mcg/minute; may be titrated rapidly (eg, up to every 5 minutes) to achieve desired hemodynamic effect; usual dosage range: 5 to 300 mcg/minute. Doses >400 mcg/minute are not recommended due to minimal added benefit and increased risk for thiocyanate toxicity (HFSA 2010).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Hypertension, acute including hypertensive crisis: Infants, Children, and Adolescents: Continuous IV infusion: Initial: 0.3 to 0.5 mcg/kg/minute, titrate every 5 minutes to desired effect; usual dose: 3 to 4 mcg/kg/minute; maximum dose: 10 mcg/kg/minute (Chandar 2012; Hegenbarth 2008; NHBPEP 2004; Park 2014); increased infusion rates are correlated with increased cyanide concentrations (Hammer 2015); a study in pediatric postoperative cardiac surgery patients found patients with rates ≥1.8 mcg/kg/minute had increased cyanide concentrations (Moffett 2008); monitor cyanide levels with prolonged use (eg, >72 hours) (NHBPEP 2004)

Cardiac output maintenance/stabilization, postresuscitation (PALS [Kleinman 2010]): Infants, Children, and Adolescents: Continuous IV infusion: Initial: 0.5 to 1 mcg/kg/minute, titrate to desired effect; maximum dose: 8 mcg/kg/minute

Reconstitution

Nitropress: Prior to administration, nitroprusside sodium should be further diluted by diluting 50 mg in 250 to 1,000 mL of D5W (preferred), LR, or NS.

Nipride RTU vial: Premixed solutions are available.

Use only clear solutions; solutions of nitroprusside exhibit a color described as brownish, brown, brownish-pink, light orange, and straw. Solutions are highly sensitive to light. Exposure to light causes decomposition, resulting in a highly colored solution of orange, dark brown or blue. A blue color indicates almost complete decomposition. Do not use discolored solutions (eg, blue, green, red) or solutions in which particulate matter is visible.

Prepared solutions should be wrapped as soon as possible with aluminum foil or other opaque material to protect from light.

Administration

IV: IV infusion only; infusion pump required. Due to potential for excessive hypotension, continuously monitor patient’s blood pressure during therapy. Product should always be protected from light, even during administration.

Storage

Nitropress, Nipride RTU vial: Store at 20°C to 25°C (68°F to 77°F). Protect from light; recommended to store in carton until used.

Stability of parenteral admixture in D5W, LR, or NS at room temperature (25°C) and at refrigeration temperature (4°C) is 24 hours.

Drug Interactions

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. 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. Consider therapy modification

Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

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

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

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

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Nitroprusside. Monitor therapy

Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. 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. Avoid combination

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

Dexmethylphenidate: May diminish the therapeutic effect of Antihypertensive Agents. Monitor therapy

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

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

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

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

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

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

Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

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

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

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

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. 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. 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. Consider therapy modification

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

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

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Nitroprusside. 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. Monitor therapy

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

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

Riociguat: May enhance the hypotensive effect of Nitroprusside. Avoid combination

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. Monitor therapy

Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Adverse Reactions

Frequency not defined:

Cardiovascular: Bradycardia, ECG changes, flushing, palpitations, severe hypotension, substernal pain, tachycardia

Central nervous system: Apprehension, dizziness, headache, increased intracranial pressure, restlessness

Dermatologic: Diaphoresis, localized erythematous streaking, skin rash

Endocrine & metabolic: Hypothyroidism

Gastrointestinal: Abdominal pain, intestinal obstruction, nausea, retching

Hematologic & oncologic: Decreased platelet aggregation, methemoglobinemia

Local: Irritation at injection site

Neuromuscular & skeletal: Muscle twitching

Warnings/Precautions

Concerns related to adverse effects:

• Cyanide toxicity: [US Boxed Warning]: Except when used briefly or at low (<2 mcg/kg/minute) infusion rates, nitroprusside gives rise to large cyanide quantities. Do not use the maximum dose for more than 10 minutes; if blood pressure is not controlled by the maximum rate (ie, 10 mcg/kg/minute) after 10 minutes, discontinue infusion. Monitor for cyanide toxicity via acid-base balance and venous oxygen concentration; however, clinicians should note that these indicators may not always reliably indicate cyanide toxicity. Patients at risk of cyanide toxicity include those who are malnourished, have hepatic impairment, or those undergoing cardiopulmonary bypass, or therapeutic hypothermia (Rindone 1992). Discontinue use of nitroprusside if signs and/or symptoms of cyanide toxicity (eg, metabolic acidosis, decreased oxygen saturation, bradycardia, confusion, convulsions) occur. Although not routinely done, sodium thiosulfate has been co-administered with nitroprusside using a 10:1 ratio of sodium thiosulfate to nitroprusside when higher doses of nitroprusside are used (eg, 4 to 10 mcg/kg/minute) for extended periods of time in order to prevent cyanide toxicity (Shulz 2010; Varon 2008); thiocyanate toxicity may still occur with this approach (Rindone 1992). The use of other agents (eg, clevidipine, labetalol, nicardipine) should be considered if blood pressure is not controlled with nitroprusside.
• Hypotension: [US Boxed Warning]: Excessive hypotension resulting in compromised perfusion of vital organs may occur; continuous blood pressure monitoring by experienced personnel is required.
• Increased intracranial pressure: Use may elevate intracranial pressure; in patients whose intracranial pressure is already elevated, use only with extreme caution.

Methemoglobinemia: Nitroprusside can cause a dose-dependent conversion of hemoglobin to methemoglobin. Methemoglobinemia should be suspected in any patient receiving >10 mg/kg of nitroprusside and exhibiting signs of impaired oxygen delivery despite adequate cardiac output and arterial pO₂. Symptomatic patients, regardless of methemoglobin level should be treated with methylene blue (first-line). Treatment is suggested if level is ≥30% even if asymptomatic unless patient has a preexisting condition (eg, coronary artery disease) and are incapable of tolerating reductions in oxygen carrying capacity then treatment is suggested if level reaches 10% (Cortazzo 2013).

• Thiocyanate toxicity: Can occur in patients with renal impairment or those on prolonged infusions (ie, >3 mcg/kg/minute for >72 hours).

Disease-related concerns:

• Anemia: When nitroprusside is used for controlled hypotension during surgery, correct pre-existing anemia prior to use when possible.
• Hepatic impairment: Use with extreme caution in patients with hepatic impairment.
• Hypovolemia: When nitroprusside is used for controlled hypotension during surgery, correct pre-existing hypovolemia prior to use when possible.
• Myocardial infarction: Use caution in patients with acute myocardial infarction because of hemodynamic effects and possible coronary steal.
• Renal impairment: Use with extreme caution in patients with renal impairment; use the lowest end of the dosage range; monitor thiocyanate concentrations closely.

Other warnings/precautions:

• Appropriate administration: Nitropress: [US Boxed Warning]: Solution must be further diluted with 5% dextrose in water. Do not administer by direct injection.

Monitoring Parameters

Blood pressure via arterial line and heart rate (cardiac monitor and blood pressure monitor required) (Friedrich 1995); monitor for cyanide and thiocyanate toxicity; monitor venous oxygen saturation; monitor acid-base status as acidosis can be the earliest sign of cyanide toxicity; monitor thiocyanate levels if requiring prolonged infusion (>3 days) or dose >3 mcg/kg/minute or patient has renal dysfunction; monitor cyanide blood levels (if available with appropriate turnaround time) in patients with decreased hepatic function

Consult individual institutional policies and procedures.

Pregnancy

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal studies have shown that nitroprusside may cross the placental barrier and result in fetal cyanide levels that are dose-related to maternal nitroprusside levels. However, information related to use in pregnancy is limited.

Patient Education

What is this drug used for?

• It is used to lower blood pressure.
• It is used to treat heart failure (weak heart).

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

• Acidosis like confusion, fast breathing, fast heartbeat, abnormal heartbeat, severe abdominal pain, nausea, vomiting, fatigue, shortness of breath, or loss of strength and energy.
• Methemoglobinemia like blue or gray color of the lips, nails, or skin; abnormal heartbeat; seizures; severe dizziness or passing out; severe headache; fatigue; loss of strength and energy; or shortness of breath.
• Severe headache
• Small pupils
• Severe dizziness
• Passing out
• Noise or ringing in the ears
• 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.