Nitroprusside

Nitroprusside Indications

In both adults and children with hypertension, nitroprusside infusions are used to reduce blood pressure instantly. This medication is also used to treat acute heart failure and to decrease bleeding following surgery. Sodium nitroprusside (SNP) gained FDA approval for treating severe hypertension in 1974. It became widely used as a fast-acting antihypertensive agent and is clinically used for hypertensive crises, heart failure, cardiac and vascular surgery, pediatric surgery, and other indications.

A potent, fast-acting, and titratable vasodilator, SNP is still used in certain difficult clinical situations, though it has been replaced by newer agents due to its adverse effects and toxicity.¹

FDA-authorized Sodium Nitroprusside Indication

• Acute heart failure with decompensation¹
• Acute hypertensive emergencies
• Perioperative hypotension induction (to reduce blood loss)
• Reduce bleeding during surgery²

Off-label Nitroprusside Uses

• Acute preload decrease in valvular aortic stenosis patients
• Decreasing afterload in acute mitral regurgitation
• Acute ischemic stroke is associated with hypertension. The American Heart Association suggests that blood pressure not be reduced after at least 24 hours after an ischemic stroke (unless it is over 220/120 mm Hg), as it could worsen the ischemic injury.
• Elevated cardiac output in high SVR and cardiogenic shock¹

Emerging Applications for Nitroprusside

• Prevention and treatment of “no-reflow” in percutaneous coronary intervention
• Treatment of schizophrenia symptoms¹

Vasodilator Drugs List

• Alprostadil IV
• Corlopam
• Deponit
• Fenoldopam
• Glyceryl trinitrate transdermal
• Hydralazine
• Loniten
• Minitran
• Minodyl
• Minoxidil
• Minoxidil HTN
• Nipride RTU
• Nitrocine
• NitroDur
• Nitropress
• Nylidrin
• Papaverine
• ParaTime SR
• Prostin VR Pediatric
• Sodium Nitroprusside
• Transdermal Nitroglycerin³

Drug Class Profile

Vasodilators Mechanism of Action

Vasodilator agents, such as natriuretic peptides and nitric oxide, are antihypertensive agents. Vasodilators often dilate or prevent constriction of the blood vessels, which increases blood flow to different organs.

Numerous vasodilators bind to receptors on blood vessel endothelial cells, which then stimulate calcium release. Calcium triggers the nitric oxide synthase enzyme and transforms L-arginine to NO. It diffuses out of the endothelial cells and into the vascular smooth muscle cells.

Comparing nitroprusside vs nitroglycerin, they are both vasodilators, but nitroprusside is a potent arterial and venous vasodilator, while nitroglycerin is more of a venodilator.

Phosphoglycerate kinase (GTP), which catalyzes the chemical reaction, is activated and converted to cGMP by NO. Then, cGMP turns on an enzyme called myosin-light chain phosphatase, which removes a single phosphate from myosin and actin filaments. The dephosphorylation of myosin and actin filaments permits the relaxation of vascular smooth muscle.⁴

Vasodilators Mechanism of Action by Class

Each vasodilator class has a different mechanism of action:⁴

• Angiotensin-converting enzyme or ACE inhibitors
  • These inhibitors prevent angiotensin I from converting to angiotensin II, which is a strong vasoconstrictor.
• Angiotensin Receptor Blockers (ARBs)
  • These receptor blockers prevent angiotensin II from binding to its receptor.
• Nitrates
  • These increase the amount of nitric oxide in vascular smooth muscle cells, which causes vasodilation. Nitrates dilate veins more than arteries and decrease preload.
• Calcium Channel Blockers
  • These block calcium channels in the cardiac and smooth muscles, which causes decreased muscle contractility and vasodilation.
• Minoxidil
  • This directly relaxes arteriolar smooth muscle minimally affecting the vein. Cyclic adenosine monophosphate may mediate its effects.
• Hydralazine
  • The exact mechanism for Hydralazine is still unknown.
• Beta blockers
  • Nebivolol and carvedilol are third-generation β-adrenoreceptor antagonists. They have additional endothelium-dependent vasodilating properties.

Pharmacokinetics & Pharmacodynamics

• Angiotensin-converting enzyme (ACE) Inhibitors
  • ACE inhibitors prevent the conversion of angiotensin-I to angiotensin-II and are most effective when renin production is increased. Since ACE is identical to kininase-II, which inactivates the potent endogenous vasodilator bradykinin, ACE inhibition causes a reduction in bradykinin degradation.
• Minoxidil
  • Treatment with minoxidil, a potassium channel opener, is reserved for patients with moderately severe to severe hypertension.
• Hydralazine
  • Hydralazine is chiefly used to treat severe hypertensive emergencies, primary pulmonary and malignant hypertension, and severe preeclampsia.
• Beta Blockers
  • Nebivolol and carvedilol are third generation β-adrenoreceptor antagonists. They have additional endothelium-dependent vasodilating properties.⁵

Vasodilator Warnings & Precautions

After the initiation of vasodilators, the patient’s blood pressure and heart rate must be monitored to prevent possible adverse events. Administrators should also check antinuclear antibody titers and anti-histone antibody levels if the patient is on hydralazine and develops symptoms similar to those of the lupus virus.⁴

Vasodilator Adverse Effects & Events

• ACE inhibitors
  • ACE inhibitors can cause angioedema, dry cough, teratogenicity, hyperkalemia, and hypotension.
• ARBs
  • ARBs can cause hyperkalemia, hypotension, decrease GFR, and teratogenicity.
• Nitrates
  • Can cause reflex tachycardia, headache, flushing, and orthostatic hypotension.
• Calcium Channel Blocker
  • Calcium Channel Blockers can cause gingival hyperplasia, dizziness, flushing, peripheral edema, AV block (with Non-dihydropyridines), and constipation.
• Hydralazine
  • Hydralazine can cause compensatory tachycardia, headache, angina, SLE-like symptoms (in slow acetylators), and fluid retention.
• Beta Blockers
  • Beta-blockers can cause bradycardia, dizziness, headaches, nausea, hypotension, and metabolic abnormalities.⁵

Vasodilators Contraindications

• ACE inhibitors⁴
  • ACE inhibitors are hypotensive agents but are not advised as a treatment for patients who are pregnant or who have a history of angioedema or hereditary angioedema.
• ARBs
  • ARBs are teratogens and should not be used in pregnant patients.
• Nitrates
  • Nitrates decrease preload, so the administration of nitrates would be contraindicated in a person having an inferior Myocardial infarction (right ventricular infarction).
• Calcium Channel Blocker
  • severe hypotension, hypersensitivity.
• Hydralazine
  • CAD or angina (it can cause compensatory tachycardia), mitral valve rheumatic heart disease
• Beta Blockers
  • Bradycardia, severe chronic obstructive pulmonary disease, hypotension, cardiogenic shock, and a high degree of atrioventricular block.

Drug Specific Profile

Nitroprusside Mechanism of Action

Sodium nitroprusside interferes with both the influx and the intracellular activation of calcium to cause arterial and venous relaxation. Nitroprusside, which is water-soluble salt sodium, is composed of ferrous iron complexed with nitric oxide and five cyanide ions.

As a prodrug, SNP interacts with erythrocyte sulfhydryl groups (as well as albumin and other proteins) to form nitric oxide. When nitrate oxide binds to vascular smooth muscle, it stimulates intracellular cGMP-mediated activation of protein kinase G and subsequent inactivation of myosin light chains.

This leads to vascular smooth muscle relaxation. As a result of this signaling cascade, both arteries and veins experience peripheral vasodilation (with slightly more selectivity for veins).¹

Nitroprusside Pharmacokinetics & Pharmacodynamics

• Half-life of the parent drug
  • 2 minutes, metabolite (thiocyanate): 3 days or more in individuals who have hyponatremia or poor renal function.
• Onset of action
  • < 2 minutes
• Duration
  • 1 to 10 minutes
• Metabolism
  • 100% in blood. The ferrous ion in nitroprusside molecules reacts with sulfhydryl compounds in RBCs. Then, cyanide is released and metabolized to thiocyanate in the liver and kidneys.
• Metabolites
  • Inactive thiocyanate
• Excretion
  • Metabolites (predominantly thiocyanate) are secreted primarily via urine
• Dialyzable
  • Yes⁶

Nitroprusside Warnings & Precautions

Sodium nitroprusside should not be directly injected, because it requires dilution prior to infusion. Another risk is the possible occurrence of hypotension, leading to irreversible ischemic injury or death.

Therefore, treatment requires appropriate monitoring equipment and experienced personnel. Other precautions must be taken as cyanide toxicity may occur because of the accumulation of cyanide ion.⁶

Nitroprusside Adverse Events

• Cardiovascular:
  • Bradycardia
  • Tachycardia
  • Flushing
  • Palpitations
  • Severe hypotension
  • Electrocardiographic changes
  • Substernal chest pain
  • Shortness of breath
• Central Nervous System:
  • Headache
  • Dizziness
  • Increased intracranial pressure
  • Apprehension
  • Restlessness
• Dermatologic:
  • Diaphoresis
  • Skin rash
  • Local skin irritation with erythematous streaking
• Endocrine/Metabolic:
  • Hypothyroidism
• Gastrointestinal:
  • Abdominal pain
  • Nausea
  • Vomiting/retching
• Hematologic/Oncologic:
  • Decreased platelet aggregation
  • Methemoglobinemia
• Musculoskeletal:
  • Muscle twitching¹

Nitroprusside Contraindications

• Treatment of compensatory hypertension, such as that present in arteriovenous malformations or aortic coarctation
• SNP should not be administered to patients with known insufficient cerebral perfusion for the purpose of inducing controlled perioperative hypotension.
• Low systemic vascular resistance and acute heart failure, such as septic shock
• Vitamin B12 deficiency or related disease states
• Due to their complementary cGMP-mediated mechanisms of action, SNP and phosphodiesterase inhibitors like sildenafil, tadalafil, or vardenafil should not be used at the same time.
• Known hypersensitivity to nitroprusside or any other component of the formulation¹

Nitroprusside Interactions

Drugs that may interact with Nitroprusside include medications that help lower your blood pressure.

Patients who are also taking antihypertensive medications, such as hydralazine or hexamethonium, are often sensitive to the hypotensive effect of sodium nitroprusside. The dosage needs to be adjusted downward accordingly.⁷

Nitroprusside Administration & Dosage

Adult and pediatric administration of nitroprusside sodium is conducted by injectable solution.⁶

• Nitropress
  • 25mg/mL (50mg/2mL vial) (Nitropress)
• Nipride RTU
  • 0.2mg/mL (20mg/100mL 0.9% NaCl)
  • 0.5mg/mL (50mg/100mL 0.9% NaCl)

Nitroprusside Hypertensive Crisis

Cases of hypertensive crisis are indicated for immediate blood pressure (BP) decrease during a hypertensive crisis. The initial infusion rate should be 0.3 mcg/kg/min and the administrator should assess blood pressure for at least 5 minutes before adjusting the dosage to attain the target blood pressure. The infusion rate should not exceed 10 mcg/kg/min.

The dose may be titrated upward until the desired effect is achieved, the maximum recommended infusion rate (10 mcg/km/min) is reached, or the systemic BP cannot be reduced further without risking the perfusion of vital organs.⁶

Controlled Hypotension During Surgery

Cases of hypotension during surgery are indicated for controlled hypotension to lessen bleeding. The initial infusion rate should be 0.3 mcg/kg/min and the administrator should monitor the patient’s BP for at least 5 minutes before attempting a higher or lower dose to elicit the desired BP, but should not exceed 10 mcg/kg/min.

The dose may be titrated upward until the desired effect is achieved, they reach the maximum recommended infusion rate (10 mcg/km/min), or systemic BP cannot be lowered any further without risking the perfusion of vital organs.⁶

Nitroprusside Considerations for Patients & Special Populations

Older adults may be especially sensitive to the drug’s hypotensive effects, so special caution should be taken when it is used with this population.⁸

Nitroprusside Monitoring

During the infusion of nitroprusside sodium, continuous blood pressure monitoring is preferable via an arterial line in an intensive care unit for appropriate dose titration.

References

1. Holme MR, Sharman T. Sodium Nitroprusside. In: StatPearls. StatPearls Publishing, Treasure Island (FL); 2022. PMID: 32491419.

2. Nitroprusside. DrugBank Online. Published June 13, 2005. Updated November 8, 2022. Accessed November 9, 2022.

3. Jacob D. Vasodilators: Drug class, uses, side effects, drug names. RxList. Published November 9, 2021. Accessed October 23, 2022.

4. Hariri L, Patel JB. Vasodilators. In: StatPearls. Treasure Island (FL): StatPearls Publishing; Published January 2022. Updated August 2022 2022. Accessed October 25, 2022.

5. Kirsten R, Nelson K, Kirsten D, Heintz B. Clinical pharmacokinetics of vasodilators. Clinical pharmacokinetics. 1998 Jun;34(6):457-82. DOI: 10.2165/00003088-199834060-00003

6. Nipride RTU, Nitropress (nitroprusside sodium) dosing, indications, interactions, adverse effects, and more.

7. Product Monograph: Sodium Nitroprusside Injection. Kirkland, Québec: Pfizer Canada Inc.; 2017

8. Sodium Nitroprusside. Sodium Nitroprusside, an Overview, ScienceDirect Topics.

Author Bio

Sydney Murphy, M.S., is the Associate Editor of HealthDay Physicians Briefing and a freelance science writer based in New York City. You can follow her on Twitter @SydneyLiz_Murph.