Norepinephrine Bitartrate

Name: Norepinephrine Bitartrate

Description

Norepinephrine (sometimes referred to as l-arterenol/Levarterenol or l-norepinephrine) is a sympathomimetic amine which differs from epinephrine by the absence of a methyl group on the nitrogen atom.

Norepinephrine Bitartrate is (-)-α-(aminomethyl)-3,4-dihydroxybenzyl alcohol tartrate (1:1) (salt) monohydrate and has the following structural formula:

LEVOPHED is supplied in sterile aqueous solution in the form of the bitartrate salt to be administered by intravenous infusion following dilution. Norepinephrine is sparingly soluble in water, very slightly soluble in alcohol and ether, and readily soluble in acids. Each mL contains the equivalent of 1 mg base of norepinephrine, sodium chloride for isotonicity, and not more than 2 mg of sodium metabisulfite as an antioxidant. It has a pH of 3 to 4.5. The air in the ampuls has been displaced by nitrogen gas.

Indications

For blood pressure control in certain acute hypotensive states (e.g., pheochromocytomectomy, sympathectomy, poliomyelitis, spinal anesthesia, myocardial infarction, septicemia, blood transfusion, and drug reactions).

As an adjunct in the treatment of cardiac arrest and profound hypotension.

Clinical pharmacology

LEVOPHED functions as a peripheral vasoconstrictor (alpha-adrenergic action) and as an inotropic stimulator of the heart and dilator of coronary arteries (beta-adrenergic action).

What is the most important information i should know about norepinephrine (levophed bitartrate)?

If possible before receiving norepinephrine, tell your doctor if you have high blood pressure, diabetes, coronary artery disease, circulation problems, varicose veins, overactive thyroid, asthma, or a sulfite allergy.

Also tell your doctor about all other medicines you use, especially blood pressure medication or an antidepressant.

In an emergency situation it may not be possible before you are treated to tell your caregivers about your health conditions or if you are pregnant or breast feeding. Make sure any doctor caring for you afterward knows that you have received this medication.

Tell your caregivers at once if you have a serious side effect such as cold feeling anywhere in your body, blue lips or fingernails, trouble breathing, urinating less than usual, irritation or skin changes where the medicine is injected, slow heart rate, sudden numbness or weakness, confusion, severe headache, or problems with vision, speech, or balance.

What should i avoid while receiving norepinephrine (levophed bitartrate)?

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Uses for Norepinephrine Bitartrate

Acute Hypotensive States

Used as adjunctive therapy to produce vasoconstriction and maintain BP in the management of certain acute hypotensive states (e.g., pheochromocytomectomy, sympathectomy, poliomyelitis, spinal anesthesia, MI, septicemia, blood transfusion, drug reactions).101 153 154 157 162 163

Pressor therapy is not a substitute for replacement of blood, plasma, fluids, and/or electrolytes.b Correct blood volume depletion as fully as possible before administration.b

The Surviving Sepsis Campaign International Guidelines for Management of Sepsis and Septic Shock recommend norepinephrine as the vasopressor of choice in adults with septic shock; if adequate BP not achieved, vasopressin or epinephrine may be added.153 155 158 Vasopressin also may be given in conjunction with norepinephrine to reduce dosage requirements of norepinephrine.153 155

Also used to provide vasopressor support in other types of shock (e.g., cardiogenic, hemorrhagic), generally as a temporary measure until underlying cause can be treated.152 157 158 159 160 162

In patients who are hypotensive from blood volume deficits, manufacturer states to use norepinephrine only as an emergency measure to maintain coronary and cerebral artery perfusion until blood volume replacement therapy can be completed.101

Early revascularization is standard of care in patients with cardiogenic shock; individualize use of vasopressors in this setting.161 162

Has been used to treat hypotension during spinal anesthesia; however, other vasopressors with a longer duration (e.g., phenylephrine) more commonly used.b

Advanced Cardiovascular Life Support

Used adjunctively in the management of cardiac arrest to restore and maintain adequate BP after an effective heartbeat and ventilation have been established by other means.100 101

High-quality CPR and defibrillation are the only proven interventions to increase survival to hospital discharge in ACLS.400 401 Other resuscitative efforts, including drug therapy, are considered secondary and should be performed without compromising the quality and timely delivery of chest compressions and defibrillation.400 401

Principal goal of pharmacologic therapy during cardiac arrest is to facilitate the return of spontaneous circulation (ROSC), and epinephrine is the drug of choice for this use.400 401 Vasoactive drugs such as norepinephrine may be used for hemodynamic support following resuscitation.403 404

Cautions for Norepinephrine Bitartrate

Contraindications

  • Generally contraindicated during anesthesia with cyclopropane or halogenated hydrocarbon general anesthetics.101 (See Specific Drugs under Interactions.)

  • Use in patients who are hypotensive from blood volume deficits except as an emergency measure to maintain coronary and cerebral artery perfusion until blood volume replacement therapy can be completed.101

  • Use in patients with mesenteric or peripheral vascular thrombosis, unless clinically necessary as a life-saving procedure.101

  • Use in patients with profound hypoxia or hypercapnia may be contraindicated.101 (See Arrhythmias under Cautions.)

Warnings/Precautions

Warnings

Severe Hypertension

To avoid the potential for dangerously high BP, monitor BP closely during administration.101 Headache may be a symptom of hypertension due to overdosage.101

Hypovolemia

Pressor therapy is not a substitute for replacement of blood, plasma, fluids, and/or electrolytes.b Correct blood volume depletion as fully as possible before administration.b

May be used in an emergency as an adjunct to fluid volume replacement or as a temporary supportive measure to maintain coronary and cerebral artery perfusion until volume replacement therapy can be completed, but norepinephrine must not be used as sole therapy in hypovolemic patients.b

Concomitant Drugs

Administer with extreme caution in patients receiving an MAO inhibitor or a triptyline- or imipramine-type antidepressant because severe, prolonged hypertension may result.101 (See Interactions.)

Extravasation

Because severe local adverse effects (e.g., tissue necrosis, sloughing at injection site) may occur as a result of local vasoconstriction, must avoid extravasation.101 (See Boxed Warning.)

Check site of infusion frequently for free flow and monitor infused vein for blanching.101

Risk of tissue damage is apparently very slight if infused through a plastic catheter deep into an antecubital vein.101

Avoid injection into leg veins, especially in geriatric patients or those with occlusive vascular diseases (e.g., arteriosclerosis, atherosclerosis, Buerger’s disease).101

Impairment of circulation and sloughing of tissue may also occur without obvious extravasation.101

If blanching is observed in the infused vein or if therapy is to be prolonged, consider changing the injection site periodically.101

Sensitivity Reactions

Sulfite Sensitivity

Formulations of norepinephrine bitartrate injection contain sulfites, which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.101

General Precautions

Prolonged Administration

Has caused decreased cardiac output, edema, hemorrhage, focal myocarditis, subpericardial hemorrhage, necrosis of the intestine, or hepatic and renal necrosis.b Generally occurs in patients with severe shock and it is not clear if the drug or the shock state itself was the cause.b

Vasoconstriction

Can cause severe peripheral and visceral vasoconstriction, reducing blood flow and tissue perfusion to vital organs and resulting in possible tissue hypoxia, lactic acidosis, and ischemic injury; these effects are most likely to occur in hypovolemic patients if plasma volumes are not adequately corrected.101

Cardiovascular Effects

May cause plasma volume depletion, which may result in hypotension when the drug is discontinued in the absence of blood volume replacement.101

Cardiac output may be decreased following prolonged use of the drug or administration of large doses because venous return to the heart may be diminished because of increased peripheral vascular resistance; decreased cardiac output may be especially harmful to elderly patients or those with initially poor cerebral or coronary circulation.b

Arrhythmias

May cause bradycardia (probably a reflex response to increased BP) as well as potentially fatal cardiac arrhythmias, including ventricular tachycardia and ventricular fibrillation.101

Arrhythmias are especially likely to occur in patients with severe hypoxia, or hypercapnia, or those receiving other drugs that may increase cardiac irritability such as cyclopropane or halogenated hydrocarbon general anesthetics.101 (See Specific Drugs under Interactions.)

Hypoxia, Hypercapnia, and Acidosis

Hypoxia, hypercapnia, and acidosis may reduce the effectiveness and/or increase the incidence of adverse effects of norepinephrine, and must be identified and corrected prior to or concurrently with administration of the drug.b

Specific Populations

Pregnancy

Category C.101 Use during pregnancy only if clearly indicated.101

Lactation

Not known whether norepinephrine is distributed into milk.101 Use caution.101

Pediatric Use

Safety and efficacy not established.101

Geriatric Use

Insufficient experience in patients ≥65 years of age.101 (See Geriatric Patients under Dosage and Administration.)

Do not infuse into leg veins in geriatric patients.101 (See Extravasation under Cautions.)

Common Adverse Effects

May cause headache, anxiety, arrhythmias, bradycardia, respiratory difficulty, ischemic injury, or extravasation at the infusion site.101

Actions

  • Acts predominantly by a direct effect on α-adrenergic receptors.b

  • Also stimulates β1-adrenergic receptors but not β2-adrenergic receptors.b

  • Main therapeutic effect is a clinically important increase in mean arterial pressure (MAP), with minimal change in heart rate or cardiac output.101 153 156

  • Constricts both arterial and venous blood vessels through its effect on α-adrenergic receptors.b

  • Systemic vascular resistance is increased, resulting in increased BP.b

  • Induces vasoconstriction in most vascular beds, potentially reducing blood flow to the renal, splanchnic, and cutaneous vasculature.101 152 154 158

  • Local vasoconstriction caused by the drug may result in hemostasis and/or necrosis.b

  • May reduce circulating plasma volume (especially with prolonged use).b

  • Acts on β1-adrenergic receptors in the heart, producing a positive inotropic effect on the myocardium.b 100

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