Each mL of solution contains norepinephrine bitartrate monohydrate equivalent to norepinephrine 1 mg.
Pharmacology: Norepinephrine is a sympathomimetic amine which mainly acts through direct effect on α- and β-receptor on the heart. This causes peripheral vasoconstriction (α-adrenergic action), positive inotropic effect and coronary arterial dilatation (β-adrenergic action). These actions result in an increased systemic blood pressure and coronary arterial blood flow. In myocardial infarction accompanied with hypotension, norepinephrine usually increase aortic blood pressure, coronary arterial blood flow and myocardial oxygenation, thereby helping to limit the area of myocardial ischaemia and infarction. Venous return is increased and the heart tends to resume a more normal rate and rhythm than in the hypotensive state. If hypotension persists after correction of blood volume deficits, norepinephrine helps raise the blood pressure to an optimal level and establishes a more adequate circulation. However, norepinephrine effects in β1-receptor is lower than epinephrine or isoproterenol. It is believed that α-adrenergic effect resulted from inhibition of cyclic adenosine-31,51-monophosphate (AM)-production by inhibition of adenyl cyclase enzyme, whereas β-adrenergic is produced by stimulating the activity of adenyl cyclase.
Pharmacokinetics: Absorption: Oral ingestion of norepinephrine is destroyed in GI tract and it is poorly absorbed after SC injection. After IV administration, a pressor response occurs rapidly. Norepinephrine has a short duration of action and its pressure action stops within 1-2 min after infusion is discontinued.
Distribution: Norepinephrine localises mainly in sympathetic nervous system. It can pass through the placenta but not the blood-brain barrier.
Elimination: Pharmacological action of norepinephrine are terminated primarily by uptake & metabolism in sympathetic nerve endings. It is metabolised in the liver & other tissues by a combination of reactions involving catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). The major metabolites are normetanephrine and 3-methoxy-4-hydroxy mandelic acid (vanillylmandelic acid, VMA), both are inactive. Other inactive metabolites are 3-methoxy-4-dihydroxyphenylglycol, 3,4-dihydroxymandelic acid and 3,4-dihydroxyphenylglycol. Norepinephrine metabolites are excreted in urine, primarily as sulphate conjugates and to a lesser extent, as the glucuronide conjugates. Only a small quantity of norepinephrine are excreted in the unchanged form.
To control blood pressure in acute hypotensive state (eg, pheochromocytomectomy, sympathectomy, poliomyelitis, spinal anesthesia, myocardial infarction, septicaemia, blood transfusion and drug reactions). As an adjunctive treatment of cardiac arrest and severe hypotension. To restore and maintain an adequate blood pressure after an effective heart beat & ventilation have been established by other means.
Raivas injections is a concentrated, potent drug which must be diluted in dextrose-containing solutions prior to infusion. An infusion of norepinephrine should be given into a large vein (see Precautions).
Restoration of Blood Pressure in Acute Hypotensive States: Blood volume depletion should always be corrected as soon as possible before any vasopressor is administered. When used as an emergency action, intra-aortic pressure must be maintained to prevent cerebral or coronary artery ischaemia, norepinephrine may be given before and concurrently with blood volume replacement.
Diluent: Norepinephrine should be diluted in 5% dextrose injection or 5% dextrose and sodium chloride injections. This dextrose-containing solution significantly provides protection against loss of potency due to oxidation. The administration of norepinephrine in sodium saline solution alone is not recommended. Whole blood or plasma, if indicated to raise the blood volume should be administered separately (eg, by use of a Y-tube and individual container when given simultaneously).
Average Dosage: Add 4 mL (4 mg) of norepinephrine into 1000 mL of 5% dextrose-containing solution. Each mL of this dilution contains norepinephrine base 4 mcg. Administer the solution by IV infusion. Insert the plastic IV catheter through a suitable bore needle well advanced centrally into the vein then fixed with adhesive tape. If possible, avoid a tie-in catheter technique, as this promotes stasis. IV drip chamber or other suitable metering device is required to accurately measure the rate of flow in drops/min. After observing the response to an initial dose of 2-3 mL (from 8-12 mcg of base)/min, adjust the rate of flow to establish and to maintain a low normal blood pressure (usually 80-100 mm Hg of systolic blood pressure) sufficient to maintain the circulation to vital organs. In patients with a history of hypertension, it is recommended to increase blood pressure not higher than 40 mm Hg below the preexisting systolic pressure. The average maintenance dose is 0.5-1 mL/min (2-4 mcg of base form).
High Dosage: Each person needs variation of dose to establish and maintain an adequate blood pressure. In all cases, dosage of norepinephrine should be titrated according to patient response. Occasionally, much larger or even enormous daily dose (as high as 68 mg base or 17 ampoules) may be necessary if patients remain hypotensive, but any presence of occult blood, volume depletion should be suspected and corrected when present. Monitoring of central venous pressure is usually helpful in detecting and treating this condition.
Fluid Intake: The degree of dilution depends on the requirement of clinical fluid volume. If large volume of fluid (dextrose) is needed at a flow rate that would involve an excessive dose of the pressor agent per unit of time, a solution which is more diluted than 4 mcg/mL should be used. On the other hand, when large volumes of fluid are clinically undesirable, a concentration of >4 mcg/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 gradually reduced, avoiding the abrupt withdrawal. In some of the reported cases of vascular collapse due to acute myocardial infarction, treatment was required for up to 6 days.
Adjunctive Treatment in Cardiac Arrest: Infusions of norepinephrine are usually administered IV 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 β-adrenergic-stimulating action is also thought to increase the strength and effectiveness of systolic contractions].
Average Dosage: To maintain systemic blood pressure during the management of cardiac arrest, norepinephrine is used in the same manner as described previously under Restoration of Blood Pressure in Acute Hypotensive States.
Parenteral drug products should be visually observed for any particulate matter and discolouration prior to use, whenever solution and container permit.
Do not use the solution if its colour is pinkish or darker than slightly yellow or if it contains a precipitate.
Avoid contact with iron salts, alkalis or oxidising agents.
Overdosage of norepinephrine may result in headache, severe hypertension, reflex bradycardia, marked increase in peripheral resistance and decreased cardiac output. In case of accidental overdosage, as evidenced by excessive blood pressure elevation, discontinue norepinephrine until the condition of the patient is stable.
Norepinephrine should not be given in hypotensive patients due to blood volume depletion, unless in emergency condition in order to maintain coronary and cerebral artery perfusion until blood volume replacement therapy can be done. If norepinephrine is continuously administered to maintain blood pressure in the absence of blood volume replacement, the following conditions may occur: Severe peripheral and visceral vasoconstriction, decreased renal perfusion and urine output, poor systemic blood flow despite normal blood pressure, tissue hypoxia and lactic acidosis.
Norepinephrine should not also be given to patients with mesenteric or peripheral vascular thrombosis (because of the increased risk of ischaemia and area extension of infarction), unless, in the opinion of the attending physician, the administration of norepinephrine is necessary as a life-saving procedure.
Cyclopropane and halothane anaesthetics increase cardiac autonomic irritability and therefore lead to sensitisation of myocardium to the action of norepinephrine or epinephrine administered IV. Hence, the use of norepinephrine during the administration of cyclopropane and halothane anaesthesia is generally contraindicated because of the risk of producing ventricular tachycardia or fibrillation.
The same type of cardiac arrhythmias may result from the use of norepinephrine in patients with severe hypoxia or hypercarbia.
Norepinephrine should be used with extreme caution in patients receiving monoamine oxidase inhibitors (MAOIs) or antidepressants of the triptyline or imipramine types, as it may cause severe, prolonged hypertension. Norepinephrine bitartrate injection contains sodium metabisulphite, a sulphite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulphite sensitivity in the general population is unknown. Sulphite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.
General: Avoid Hypertension: Because of the potency of norepinephrine and because of varying response to pressor substances, the possibility always exists that dangerously high blood pressure may be produced with overdoses of this pressor agent. Therefore, blood pressure should be recorded every 2 min from the time administration is started until the desired blood pressure is obtained, then every 5 min if administration is to be continued. The rate of flow must be watched constantly and the patient should never be left unattended while receiving norepinephrine. Headache may be a symptom of hypertension due to overdosage.
Site of Infusion: Whenever possible, infusions of norepinephrine should be given into a large vein, particularly on the antecubital vein, because of the risk of necrosis of the overlying skin from prolonged vasoconstriction, when administered into this vein, is apparently very slight. Some scientists have indicated that the femoral vein is also an acceptable route of administration. If possible, a catheter tie-in technique should be avoided, since the obstruction to blood flow around the tubing may cause stasis and increased local concentration of norepinephrine. Occlusive vascular diseases (eg, atherosclerosis, arteriosclerosis, diabetic endarteritis, Buerger's disease) are more likely to occur in the lower extremity than in the upper extremity. Therefore, avoid the veins of the leg in elderly patients or in those suffering from such disorders. It has been reported that gangrene occur in the lower extremity when infusions of norepinephrine were given in an ankle vein.
Extravasation: The infusion site should be checked frequently for free flow. Care should be taken to avoid extravasation of norepinephrine into the tissues, as local necrosis might ensue due to the vasoconstrictive action of Raivas. Blanching along the course of the infused vein, sometimes without obvious extravasation, has been attributed to vasa vasorum constriction with increased permeability of the vein wall, permitting some leakage. Although rare, this also may progress to superficial slough, particularly during infusion into leg veins in elderly patients or in those suffering from obliterative vascular disease. Hence, if blanching occurs, consideration should be given for periodically changing the infusion site at intervals to allow the effects of local vasoconstriction.
Antidote for Extravasation Ischaemia: To prevent sloughing and necrosis in areas in which extravasation has taken place, the area should be infiltrated as soon as possible with 10-15 mL of saline solution containing phentolamine 5-10 mg, an adrenergic-blocking agent. A syringe with a fine hypodermic needle should be used, with the solution being infiltrated liberally throughout the area, which is easily identified by its cold, hard and pallid appearance. Sympathetic blockade with phentolamine causes immediate and conspicuous local hyperaemic changes if the area is infiltrated within 12 hrs. Therefore, phentolamine should be given as soon as possible after extravasation is noted.
Carcinogenicity, Mutagenicity & Impairment of Fertility: Studies have not been established.
Use in pregnancy: Animal reproduction studies have not been conducted with norepinehrine. It is also not known whether noradrenaline can cause foetal harm when administered to a pregnant woman or can affect reproduction capacity. Norepinephrine should be given to a pregnant woman only if clearly needed.
Use in lactation: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when norepinephrine is administered to a nursing mother.
Use in children: Safety and effectiveness in paediatric patients has not been established.
Use in the elderly: Clinical studies of norepinephrine did not include sufficient numbers of subjects ≥65 years to determine whether they respond differently from younger subjects. Although clinical experience has not identified differences in responses between the elderly and younger patients, 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 therapy. Norepinephrine infusions should not be administered into the veins in the leg in elderly patients.
The following reactions can occur: Body as a whole: Ischaemic injury due to potent vasoconstrictor action and tissue hypoxia.
Cardiovascular System: Bradycardia, probably as a reflex result of a rise in blood pressure, arrhythmias.
Nervous System: Anxiety, transient headache.
Respiratory System: Respiratory difficulty.
Skin and Appendages: Extravasation necrosis at injection site.
Prolonged administration of any potent vasopressor may result in plasma volume depletion which should be continuously corrected by appropriate fluid and electrolyte replacement therapy. If plasma volumes are not corrected, hypotension may recur when norepinephrine is discontinued, or blood pressure may be maintained at the risk of severe peripheral and visceral vasoconstriction (eg, decreased renal perfusion) with diminution in blood flow and tissue perfusion with subsequent tissue hypoxia and lactic acidosis and possible ischaemic injury. Gangrene of extremities has been rarely reported. Overdoses or conventional doses in hypersensitive persons (eg, hyperthyroid patients) cause severe hypertension with violent headache, photophobia, stabbing retrosternal pain, pallor, intense sweating and vomiting.
The administration of norepinephrine in patients receiving cyclopropane and halothane anaesthesia may increase cardiac irritability and may lead to arrhythmia. If pressor drug is needed during the usage of general anesthetic drugs, it is recommended to give a drug with minimal effect of cardiac stimulation eg, methoxamine or phenylephrine. If arrythmia occurs, β-adrenergic blocking agents eg, propranolol, should be given. It should be considered that digitalis also can increase sensitivity of myocardium to the effect of sympathomimetic drugs. The same type of cardiac arrhythmias may result from the use of norepinephrine in patients with severe hypoxia or hypercarbia. Norepinephrine should be used with extreme caution in patients receiving monoamine oxidase inhibitors (MAOIs) or antidepressants of the triptyline or imipramine types, because severe, prolonged hypertension may result.
The administration of furosemide or other diuretics may reduce the ability of artery to give response to pressor agents eg, norepinephrine.
Store below 30°C. Protect from light.
C01CA03 - norepinephrine ; Belongs to the class of adrenergic and dopaminergic cardiac stimulants excluding glycosides. Used in the treatment of hypotension.
Infusion (amp) 1 mg/mL x 4 mL x 5's.