Nitropress

Nitropress is a prescription medication used to treat high blood pressure (hypertention) and congestive heart failure.

Nitropress belongs to a group of drugs called antihypertensives. These work by relaxing smooth muscle of blood vessels which causes dilation of arteries and veins. This dilation leads to lower blood pressure.

This medication is available in an injectable form to be given directly into a vein by a healthcare professional.

Common side effects of Nitropress include excessively low blood pressure (hypotension), cyanide toxicity, and injection site irritation.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Tell your caregivers at once if you have a serious side effect such as:

• feeling like you might pass out, even while lying down;

• gasping, struggling to breathe, or shallow breathing;

• confusion, ringing in your ears;

• dizziness with nausea and vomiting, rapid breathing, seizure (convulsions);

• fast, slow, or uneven heart rate;

• numb or cold feeling in your arms and legs; or

• chills, sweating, tremors, twitching, overactive reflexes.

Less serious side effects may include:

• mild skin rash;

• mild stomach pain or nausea;

• warmth, redness, or tingly feeling under your skin;

• darkening or deeper color of veins through your skin; or

• irritation around the IV needle.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Tell your doctor if you take any type of blood pressure medication.

There may be other drugs that can interact with nitroprusside. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Administration

Administer by IV infusion only.600

Administer in a setting with equipment and personnel available to continuously monitor blood pressure.600

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV infusion using a controlled-infusion device to allow precise measurement of flow rate.600

Injection concentrate (25 mg/mL) must be further diluted prior to IV infusion.600 Dilute contents of one vial (50 mg) in 250–1000 mL of 5% dextrose injection.600 Vials are for single use only.600

Protect from light by promptly wrapping the container in aluminum foil or other opaque material;600 it is not necessary to cover the infusion drip chamber or tubing.600

Adjust rate to maintain the desired hypotensive effect, determined by continuous monitoring of BP, using a continually reinflated sphygmomanometer or, preferably, an intra-arterial pressure sensor.600

When sodium nitroprusside is used in heart failure, titrate rate based on results of invasive hemodynamic monitoring and urine output.600

Dosage

Pediatric Patients

Initially, 0.3 mcg/kg per minute; gradually titrated upward every few minutes until adequate BP control is achieved or the maximum infusion rate of 10 mcg/kg per minute is reached.600 Usual dosage is 3 mcg/kg (range of 0.1–10 mcg/kg) per minute.205 207 600

Discontinue immediately if adequate reduction in BP is not achieved within 10 minutes in patients receiving the maximum recommended infusion rate of 10 mcg/kg per minute.600

Adults

Initially, 0.3 mcg/kg per minute; gradually titrated upward every few minutes until adequate BP control is achieved or the maximum rate of infusion of 10 mcg/kg per minute is reached.600 Usual dosage is 3 mcg/kg (range of 0.1–10 mcg/kg) per minute.207 600

Management of hypertensive emergency: Goal is to reduce mean arterial BP by no more than 25% within minutes to 1 hour, followed by further reduction if stable toward 160/100 to 110 mm Hg within the next 2–6 hours; avoid excessive declines in pressure.500 If this BP is well tolerated and the patient is clinically stable, further gradual reductions toward normal can be implemented in the next 24–48 hours.500

Patients with aortic dissection: Goal is to reduce systolic pressure to <100 mm Hg if tolerated.500

Discontinue immediately if adequate reduction in BP is not achieved within 10 minutes in patients receiving the maximum recommended infusion rate of 10 mcg/kg per minute.600

Prescribing Limits

Pediatric Patients

Maximum 10 mcg/kg per minute.205 207 600

Prolonged infusions should not exceed rate of 3 mcg/kg per minute; monitor thiocyanate concentrations if this rate is exceeded for prolonged periods.600

Adults

Maximum 10 mcg/kg per minute.207 600

Prolonged infusions should not exceed rate of 3 mcg/kg per minute; monitor thiocyanate concentrations if this rate is exceeded for prolonged periods.600

Special Populations

Renal Impairment

Anuric patients: Prolonged infusions should not exceed rate of 1 mcg/kg per minute (to maintain thiocyanate concentrations <60 mcg/mL).600

In the U.S.

• Nipride RTU
• Nitropress

Available Dosage Forms:

• Solution
• Powder for Solution

Therapeutic Class: Peripheral Vasodilator

Sodium nitroprusside injection is used for lowering of blood pressure immediately in adults and children with high blood pressure. This medicine is also used to reduce bleeding during surgery, and treats acute heart failure. This medicine is a direct-acting vasodilator.

This medicine is to be given only by or under the direct supervision of your doctor.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

The principal pharmacological action of sodium nitroprusside is relaxation of vascular smooth muscle and consequent dilatation of peripheral arteries and veins. Other smooth muscle (e.g., uterus, duodenum) is not affected. Sodium nitroprusside is more active on veins than on arteries, but this selectivity is much less marked than that of nitroglycerin. Dilatation of the veins promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing left ventricular end diastolic pressure and pulmonary capillary wedge pressure (preload). Arteriolar relaxation reduces systemic vascular resistance, systolic arterial pressure, and mean arterial pressure (afterload). Dilatation of the coronary arteries also occurs.

In association with the decrease in blood pressure, sodium nitroprusside administered intravenously to hypertensive and normotensive patients produces slight increases in heart rate and a variable effect on cardiac output. In hypertensive patients, moderate doses induce renal vasodilatation roughly proportional to the decrease in systemic blood pressure, so there is no appreciable change in renal blood flow or glomerular filtration rate.

In normotensive subjects, acute reduction of mean arterial pressure to 60-75 mm Hg by infusion of sodium nitroprusside caused a significant increase in renin activity. In the same study, ten renovascular-hypertensive patients given sodium nitroprusside had significant increases in renin release from the involved kidney at mean arterial pressures of 90-137 mm Hg.

The hypotensive effect of sodium nitroprusside is seen within a minute or two after the start of an adequate infusion, and it dissipates almost as rapidly after an infusion is discontinued. The effect is augmented by ganglionic blocking agents and inhaled anesthetics.

Pharmacokinetics and Metabolism: Infused sodium nitroprusside is rapidly distributed to a volume that is approximately coextensive with the extracellular space. The drug is cleared from this volume by intraerythrocytic reaction with hemoglobin (Hgb), and sodium nitroprusside’s resulting circulatory half-life is about 2 minutes.

The products of the nitroprusside/hemoglobin reaction are cyanmethemoglobin (cyanmetHgb) and cyanide ion (CN-). Safe use of sodium nitroprusside injection must be guided by knowledge of the further metabolism of these products.

As shown in the diagram below, the essential features of nitroprusside metabolism are

Cyanide ion is normally found in serum; it is derived from dietary substrates and from tobacco smoke.

Cyanide binds avidly (but reversibly) to ferric ion (Fe+++), most body stores of which are found in erythrocyte methemoglobin (metHgb) and in mitochondrial cytochromes. When CN– is infused or generated within the bloodstream, essentially all of it is bound to methemoglobin until intraerythrocytic methemoglobin has been saturated.

When the Fe+++ of cytochromes is bound to cyanide, the cytochromes are unable to participate in oxidative metabolism. In this situation, cells may be able to provide for their energy needs by utilizing anaerobic pathways, but they thereby generate an increasing body burden of lactic acid. Other cells may be unable to utilize these alternative pathways, and they may die hypoxic deaths.

CN– levels in packed erythrocytes are typically less than 1 μmol/L (less than 25 mcg/L); levels are roughly doubled in heavy smokers.

At healthy steady state, most people have less than 1% of their hemoglobin in the form of methemoglobin. Nitroprusside metabolism can lead to methemoglobin formation (a) through dissociation of cyanmethemoglobin formed in the original reaction of sodium nitroprusside with Hgb and (b) by direct oxidation of Hgb by the released nitroso group. Relatively large quantities of sodium nitroprusside, however, are required to produce significant methemoglobinemia.

At physiologic methemoglobin levels, the CN– binding capacity of packed red cells is a little less than 200 μmol/L (5 mg/L). Cytochrome toxicity is seen at levels only slightly higher, and death has been reported at levels from 300 to 3000 μmol/L (8–80 mg/L). Put another way, a patient with a normal red-cell mass (35 mL/kg) and normal methemoglobin levels can buffer about 175 mcg/kg of CN–, corresponding to a little less than 500 mcg/kg of infused sodium nitroprusside.

Some cyanide is eliminated from the body as expired hydrogen cyanide, but most is enzymatically converted to thiocyanate (SCN–) by thiosulfate-cyanide sulfur transferase (rhodanase, EC 2.8.1.1), a mitochondrial enzyme. The enzyme is normally present in great excess, so the reaction is rate-limited by the availability of sulfur donors, especially thiosulfate, cystine, and cysteine.

Thiosulfate is a normal constituent of serum, produced from cysteine by way of β-mercaptopyruvate. Physiological levels of thiosulfate are typically about 0.1 mmol/L (11 mg/L), but they are approximately twice this level in pediatric and adult patients who are not eating. Infused thiosulfate is cleared from the body (primarily by the kidneys) with a half-life of about 20 minutes.

When thiosulfate is being supplied only by normal physiologic mechanisms, conversion of CN– to SCN– generally proceeds at about 1 mcg/kg/min. This rate of CN– clearance corresponds to steady-state processing of a sodium nitroprusside infusion of slightly more than 2 mcg/kg/min. CN– begins to accumulate when sodium nitroprusside infusions exceed this rate.

Thiocyanate (SCN–) is also a normal physiological constituent of serum, with normal levels typically in the range of 50-250 μmol/L (3-15 mg/L). Clearance of SCN– is primarily renal, with a half-life of about 3 days. In renal failure, the half-life can be doubled or tripled.

Clinical Trials: Baseline-controlled clinical trials have uniformly shown that sodium nitroprusside has a prompt hypotensive effect, at least initially, in all populations. With increasing rates of infusion, sodium nitroprusside has been able to lower blood pressure without an observed limit of effect.

Clinical trials have also shown that the hypotensive effect of sodium nitroprusside is associated with reduced blood loss in a variety of major surgical procedures.

In patients with acute congestive heart failure and increased peripheral vascular resistance, administration of sodium nitroprusside causes reductions in peripheral resistance, increases in cardiac output, and reductions in left ventricular filling pressure.

Many trials have verified the clinical significance of the metabolic pathways described above. In patients receiving unopposed infusions of sodium nitroprusside, cyanide and thiocyanate levels have increased with increasing rates of sodium nitroprusside infusion. Mild to moderate metabolic acidosis has usually accompanied higher cyanide levels, but peak base deficits have lagged behind the peak cyanide levels by an hour or more.

Progressive tachyphylaxis to the hypotensive effects of sodium nitroprusside has been reported in several trials and numerous case reports. This tachyphylaxis has frequently been attributed to concomitant cyanide toxicity, but the only evidence adduced for this assertion has been the observation that in patients treated with sodium nitroprusside and found to be resistant to its hypotensive effects, cyanide levels are often found to be elevated. In the only reported comparisons of cyanide levels in resistant and nonresistant patients, cyanide levels did not correlate with tachyphylaxis. The mechanism of tachyphylaxis to sodium nitroprusside remains unknown.

Pediatric: The effects of sodium nitroprusside to induce hypotension were evaluated in two trials in pediatric patients less than 17 years of age. In both trials, at least 50% of the patients were pre-pubertal, and about 50% of these pre-pubertal patients were less than 2 years of age, including 4 neonates. The primary efficacy variable was the mean arterial pressure (MAP).

There were 203 pediatric patients in a parallel, dose-ranging study (Study 1). During the 30 minute blinded phase, patients were randomized 1:1:1:1 to receive sodium nitroprusside 0.3, 1, 2, or 3 μg/kg/min. The infusion rate was increased step-wise to the target dose rate (i.e., 1/3 of the full rate for the first 5 minutes, 2/3 of the full rate for the next 5 minutes, and the full dose rate for the last 20 minutes). If the investigator believed that an increase to the next higher dose rate would be unsafe, the infusion remained at the current rate for the remainder of the blinded infusion. Since there was no placebo group, the change from baseline likely overestimates the true magnitude of blood pressure effect. Nevertheless, MAP decreased 11 to 20 mmHg from baseline across the four doses (Table 1).

There were 63 pediatric patients in a long-term infusion trial (Study 2). During an open-label phase (12 to 24 hours), sodium nitroprusside was started at ≤0.3 μg/kg/min and titrated according to the BP response. Patients were then randomized to placebo or to continuing the same dose of sodium nitroprusside. The average MAP was greater in the control group than in the sodium nitroprusside group for every time point during the blinded withdrawal phase, demonstrating that sodium nitroprusside is effective for at least 12 hours. In both studies, similar effects on MAP were seen in all age groups.

Sodium nitroprusside is indicated for the immediate reduction of blood pressure of adult and pediatric patients in hypertensive crises. Concomitant longer-acting antihypertensive medication should be administered so that the duration of treatment with sodium nitroprusside can be minimized.

Sodium nitroprusside is also indicated for producing controlled hypotension in order to reduce bleeding during surgery.

Sodium nitroprusside is also indicated for the treatment of acute congestive heart failure.

Rx only

NDC 0187-4302-02

2 mL Single Dose Fliptop Vial

Nitropress®

Sodium Nitroprusside

Injection

50 mg/2 mL Vial

(25 mg/mL)

For IV infusion only.

Must be diluted.

Potent drug: Monitor

blood pressure before

and during administration

VALEANT