Norepinephrine

Norepinephrine is a Sympathomietic Catecholamine belonging to Alpha and Beta-adrenergic agonists.

Norepinephrine is approved for the treatment of acute hypotensive states (e.g., pheochromocytomectomy, sympathectomy, poliomyelitis, spinal anesthesia, myocardial infarction, septicemia, blood transfusion, and drug reactions). Norepinephrine is also indicated as an adjunct in the treatment of cardiac arrest and profound hypotension.

The absorption of Norepinephrine through the Oral route is Destroyed in the GI tract, and through Subcutaneous route is poorly absorbed. The Distribution of Norepinephrine mainly localise in sympathetic nervous tissue which crosses the placenta but not the blood-brain barrier. It gets metabolised in the liver and in other tissues by the enzymes catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) and gets excreted Via urine (mainly as metabolites).

The common side effects associated with Norepinephrine include Hypertension, headache, peripheral ischaemia, bradycardia, arrhythmias, anxiety, skin necrosis (with extravasation), dyspnoea, respiratory difficulty.

Norepinephrine is available in the form of dosage forms such as injection solution.

Noepinephrine is available in India, Italy, US, Australia.

Norepinephrine, acts as a Sympathomietic Catecholamine Norepinephrine works by improving cardiac contractility (inotropy), cardiac relaxation (lusitropy), and inducing vasodilation and has the overall effect of increased cardiac output, improvement of left ventricle-arterial coupling, and enhanced cardiac mechanical efficiency

Norepinephrine is a direct-acting sympathomimetic which stimulates β1- and α-adrenergic receptors. Its α-agonist effect causes vasoconstriction, thereby raising systolic and diastolic BP with reflex slowing of heart rate.

The Duration of Action for Norepinephrine occurs within 5-10 minutes.

The onset of action of norepinephrine was found within 1-2 minutes.

The Cmax in blood reached upto 82 μg ml 1

• For Injection Solution:

Noradrenaline (Norepinephrine) should only be administered as an intravenous infusion via a central venous catheter to minimize the risk of extravasation and subsequent tissue necrosis. Noradrenaline (Norepinephrine) should be infused at a controlled rate using an infusion pump.

Norepinephrine is approved for for the treatment of acute hypotensive states (e.g., pheochromocytomectomy, sympathectomy, poliomyelitis, spinal anesthesia, myocardial infarction, septicemia, blood transfusion, and drug reactions). Norepinephrine is also indicated as an adjunct in the treatment of cardiac arrest and profound hypotension.

Norepinephrine provides a strong stimulation of alpha receptors in blood vessels at which these are counter-extracted. Norepinephrine also has an effect on beta-1 receptors in the heart leading to a positive inotropic and initially positive chronotropic effect. The increase in blood pressure may cause a reflex reduction in heart rate. Vasoconstriction may lead to decreased blood flow in the kidneys, liver, skin and smooth muscle. Local constriction of the vessels may cause hemostasis and/or necrosis.

Norepinephrine is approved for use in the following clinical indications:

• Acute Hypotensive States

Blood volume depletion should always be corrected as fully as possible before any vasopressor is administered. When, as an emergency measure, intraaortic pressures must be maintained to prevent cerebral or coronary artery ischemia, Norepinephrine can be administered before and concurrently with the blood volume replacement.

Diluent

Norepinephrine should be diluted in 5 percent dextrose injection or 5 percent dextrose and sodium chloride injections. These dextrose containing fluids are protection against significant loss of potency due to oxidation. Administration in saline solution alone is not recommended. Whole blood or plasma, if indicated to increase blood volume, should be administered separately (for example, by use of a Y-tube and individual containers if given simultaneously).

Average Dosage

Add a 4 mL ampul (4 mg) of Norepinephrine to 1,000 mL of a 5 percent dextrose containing solution. Each mL of this dilution contains 4 mcg of the base of Norepinephrine. Give this solution by intravenous infusion. Insert a plastic intravenous catheter through a suitable bore needle well advanced centrally into the vein and securely fixed with adhesive tape, avoiding, if possible, a catheter tie-in technique as this promotes stasis. An IV drip chamber or other suitable metering device is essential to permit an accurate estimation of the rate of flow in drops per minute. After observing the response to an initial dose of 2 mL to 3 mL (from 8 mcg to 12 mcg of base) per minute, adjust the rate of flow to establish and maintain a low normal blood pressure (usually 80 mm Hg to 100 mm Hg systolic) sufficient to maintain the circulation to vital organs. In previously hypertensive patients, it is recommended that the blood pressure should be raised no higher than 40 mm Hg below the preexisting systolic pressure. The average maintenance dose ranges from 0.5 mL to 1 mL per minute (from 2 mcg to 4 mcg of base).

High Dosage

Great individual variation occurs in the dose required to attain and maintain an adequate blood pressure. In all cases, dosage of Norepinephrine should be titrated according to the response of the patient. Occasionally much larger or even enormous daily doses (as high as 68 mg base or 17 ampuls) may be necessary if the patient remains hypotensive, but occult blood volume depletion should always be suspected and corrected when present. Central venous pressure monitoring is usually helpful in detecting and treating this situation.

Fluid Intake

The degree of dilution depends on clinical fluid volume requirements. If large volumes of fluid (dextrose) are needed at a flow rate that would involve an excessive dose of the pressor agent per unit of time, a solution more dilute than 4 mcg per mL should be used. On the other hand, when large volumes of fluid are clinically undesirable, a concentration greater than 4 mcg per mL may be necessary.

Duration of Therapy

The infusion should be continued until adequate blood pressure and tissue perfusion are maintained without therapy. Infusions of Norepinephrine should be reduced gradually, avoiding abrupt withdrawal. In some of the reported cases of vascular collapse due to acute myocardial infarction, treatment was required for up to six days.

Although not approved there have been certain off label indication documented for the treatment of norepinephrine which includes:

• Adjunctive Treatment in Cardiac Arrest

Infusions of Norepinephrine are usually administered intravenously during cardiac resuscitation to restore and maintain an adequate blood pressure after an effective heartbeat and ventilation have been established by other means. Norepinephrine’s powerful beta-adrenergic stimulating action is also thought to increase the strength and effectiveness of systolic contractions once they occur. Average Dosage To maintain systemic blood pressure during the management of cardiac arrest, Norepinephrine is used in the same manner as described under Restoration of Blood Pressure in Acute Hypotensive States. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to use, whenever solution and container permit. Do not use the solution if its color is pinkish or darker than slightly yellow or if it contains a precipitate. Avoid contact with iron salts, alkalis, or oxidizing agents.

The dosage and the duration of treatment should be as per the clinical judgment of the treating physician

Norepineohrine is available in dosage strength as 1mg/ml.

Norepinephrine is available in the form of injection solution.

Norepinephrine should be used for the treatment in short-term management of congestive heart failure.

Heart Failure: It has been observed that the low-salt Dietary Approaches to Stop Heart Failure (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable.

The dietary restriction should be individualized as per the patient requirements.

Norepinephrine may be contraindicated in the following

● There are no absolute contraindications to the administration of norepinephrine.

● Norepinephrine use may be contraindicated to treat hypotension, likely secondary to cardiogenic mechanisms. Additionally, norepinephrine is probably not the best agent for hypotension, primarily related to hypovolemia. However, the FDA states that its use could be considered in the low volume states, but only as an emergency measure for maintaining coronary or cerebral perfusion pressure while waiting for appropriate volume resuscitation.

● Generally, norepinephrine should be avoided in patients with mesenteric or peripheral vascular thrombosis as the subsequent vasoconstriction will increase the area of ischemia and infarction.

● Profound hypoxia or hypercarbia can sensitize the myocardium to unstable arrhythmias, which could be exacerbated or even initiated by norepinephrine - this is also the case with specific anesthetic agents, such as halothane and cyclopropane.

● The preparation of norepinephrine, typically utilized in critical care settings, contains sodium metabisulfite, which may cause allergic reactions in susceptible individuals. This effect may be more common in asthmatics.

● Care is necessary when using norepinephrine concomitantly with monoamine oxidase inhibitors or amitriptyline and imipramine-type antidepressants. Combining any of these drugs can lead to severe and prolonged hypertension.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

Warning:

Noradrenaline is contraindicated in hypotensive patients in whom circulatory collapse is associated with hypovolaemia except as an emergency measure to maintain supply to the coronary and cerebral arteries until blood volume replacement therapy can be instituted.

Norepinephrine is intended for infusion via a central venous catheter only. As such, the risk of extravasation and subsequent tissue necrosis is very limited. The infusion site should be checked frequently. However, if extravasation occurs, the infusion should be stopped immediately and the area should be infiltrated with phentolamine without delay, monitored closely for improvement and re-assessed for further treatment to reverse the ischemic effect.

Precautions for use:

Norepinephrine should not be used for initiating vasopressor treatment.

In general, cautious evaluation is recommended in the following cases of hypotension and hypoperfusion, in which a reduction in the dose of noradrenaline may be required:

Major left ventricular dysfunction associated with acute hypotension. Supportive therapy should be initiated simultaneously with diagnostic evaluation. Noradrenaline should be reserved for patients with cardiogenic shock and refractory hypotension, in particular those without elevated systemic vascular resistance.

• Hypotensive patients diagnosed with coronary, mesenteric or peripheral vascular thrombosis, myocardial infarction or Prinzmetal's variant angina. Particular caution should be observed as noradrenaline may increase the associated ischaemia and extend the area of infarction.

• Occurrence of heart rhythm disorders during noradrenaline therapy.
• Caution is advised in patients with hyperthyroidism or diabetes mellitus.
• In cases where it is necessary to administer noradrenaline at the same time as total blood or plasma, the latter must be administered in a separate drip.

Consumption of alcohol is not recommended while receiving this medicine as it may gain the risk of adverse effects and lowers the blood pressure.

This medicine is not recommended for use in breastfeeding women unless necessary. 

Pregnancy Category (FDA):

● Pregnancy Category C

● Animal reproduction studies have not been conducted with Norepinephrine. It is also not known whether Norepinephrine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Norepinephrine should be given to a pregnant woman only if clearly needed.

Maintain a low salt diet and minimize eating processed foods as they contain more sodium. Try to replace Salt with spices or herbs to add flavour to the food.

The adverse reactions related to molecule Norepinephrine can be categorized as

• Common Adverse effects:

Hypertension, headache, peripheral ischaemia, bradycardia, arrhythmias, anxiety, skin necrosis (with extravasation), dyspnoea, respiratory difficulty.

• Less Common adverse effects:

Blue lips and fingernails, Confusion, Coughing that sometimes produces a pink frothy sputum, Difficult, fast, noisy breathing, Dizziness, fainting, or lightheadedness when getting up suddenly from a lying or sitting position

• Rare adverse effects:

Bradycardia, decompensated heart failure, cardiac arrest, and heart block.

The clinically relevant drug interactions of Norepinephrine is briefly summarized here.

Guanethidine, methyldopa, reserpine, TCAs may increase pressor response to norepinephrine.

Potentially Fatal: Increased risk of arrhythmias with cocaine, cyclopropane or halogenated hydrocarbon anaesthetics. Hypertensive crisis may occur with MAOIs. Hypertensive effects may be increased by nonselective β-blockers.

Patients with Hepatic Impairment: There are no dose modifications required for provided in the manufacturer's labeling for patients with hepatic impairment.

Patients with Renal Impairment: There are no dosage modifications provided per the manufacturer's labeling for patients with renal impairment.

Pregnancy Considerations: A literature review, including a few case reports and small trials involving norepinephrine in pregnant women, has not identified an increased risk of miscarriage or adverse maternal or fetal outcomes. In addition, delaying treatment in pregnant women with hypotension associated with septic shock may increase the risk of maternal and fetal morbidity and mortality. Therefore, clinicians should not withhold life-saving treatment for the pregnant woman due to potential risks regarding the consequences of norepinephrine on the fetus.

Breastfeeding Considerations: Norepinephrine inhibits the synthesis of beta-casein via stimulation of adrenergic beta-2 receptors. Animal data indicate that norepinephrine can decrease serum prolactin, reduce milk production, and inhibit the release of oxytocin, which inhibits milk ejection. Because of its poor oral bioavailability and short half-life, any norepinephrine in milk is unlikely to affect the infant. High intravenous doses of norepinephrine might reduce milk production and decrease the concentration of beta-casein in milk.

Geriatic Use

● Clinical studies of Norepinephrine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from the younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

● Norepinephrine infusions should not be administered into the veins in the leg in elderly patients.

Signs and Symptoms

● Overdosage with Norepinephrine may result in headache, severe hypertension, reflex bradycardia, marked increase in peripheral resistance, and decreased cardiac output.

Management

● In case of accidental overdosage, as evidenced by excessive blood pressure elevation, discontinue Norepinephrine until the condition of the patient stabilizes.

Pharmacodynamics:

The primary pharmacodynamic effects of norepinephrine are cardiac stimulation and vasoconstriction. Cardiac output is generally unaffected, although it can be reduced, and total peripheral resistance is also elevated. The elevation in resistance and pressure result in reflex vagal activity, which slows the heart rate and gain stroke volume. The elevation in vascular tone or resistance reduces blood flow to the major abdominal organs as well as to skeletal muscle. Coronary blood flow is substantially increased secondary to the indirect effects of alpha stimulation. After intravenous administration, a pressor response occurs rapidly and reaches steady state within 5 minutes. The pharmacologic actions of norepinephrine are terminated primarily by uptake and metabolism in sympathetic nerve endings. The pressor action stops within 1 to 2 minutes after the infusion is discontinued.

Pharmacokinetics :

• Absorption

Following initiation of intravenous infusion, the steady state plasma concentration is achieved in 5 min.

• Distribution

Plasma protein binding of norepinephrine is approximately 25%. It is mainly bound to plasma albumin and to a smaller extent to prealbumin and alpha 1-acid glycoprotein. The volume of distribution is 8.8 L. Norepinephrine localizes mainly in sympathetic nervous tissue. It crosses the placenta but not the blood-brain barrier.

• Metabolism

Norepinephrine is metabolized in the liver and other tissues by a combination of reactions involving the enzymes catechol-O-methyltransferase (COMT) and MAO. The major metabolites are normetanephrine and 3 methoxyl-4-hydroxy mandelic acid (vanillylmandelic acid, VMA), both of which are inactive. Other inactive metabolites include 3-methoxy-4-hydroxyphenylglycol, 3,4-dihydroxymandelic acid, and 3,4 dihydroxyphenylglycol.

• Elimination

The mean half-life of norepinephrine is approximately 2.4 min. The average metabolic clearance is 3.1 L/min

• https://www.mims.com/philippines/drug/info/norepinephrine?mtype=generic
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• https://www.safercare.vic.gov.au/clinical-guidance/critical/noradrenaline-norepinephrine#:~:text=Onset of action: 1–2 minutes.&text=Duration of action: 5–10 minutes.&text=Half-life: 3 minutes.

• https://www.ncbi.nlm.nih.gov/books/NBK537259/#article-25972.s2
• BUNNEY WE, DAVIS JM. Norepinephrine in Depressive Reactions: A Review. Arch Gen Psychiatry. 1965;13(6):483–494. doi:10.1001/archpsyc.1965.01730060001001