The P-I-E-N-O Parkinsn's List Drug Database
norepinephrine / LevophedTM
VASOCONSTRICTOR:
Increase systemic blood pressure
Description: Norepinephrine is a potent vasoconstrictor and inotrope. It is an endogenous catecholamine synthesized in the adrenal medulla that is the biochemical precursor of epinephrine. Norepinephrine is the transmitter of most sympathetic postganglionic fibers of the CNS. The naturally occurring form of norepinephrine as well as the commercial formulation is available only as the levorotatory isomer, which is several times more potent than the dextrorotatory isomer, thus allowing the most potent form of the medication to be administered. As with epinephrine, the investigation of norepinephrine's pharmacologic effects and synthesis dates back into the late 1880s. Norepinephrine was approved by the FDA at its inception in 1938.
Mechanism of Action: Norepinephrine acts predominantly on ›-adrenergic receptors to produce constriction of resistance and capacitance vessels, thereby increasing systemic blood pressure and coronary artery blood flow. Norepinephrine also acts on œA-receptors, although quantitatively less than either epinephrine or isoproterenol. In relatively lower doses, the cardiac-stimulant effect of norepinephrine is predominant; with larger doses, the vasoconstrictor effect predominates.
Similar to epinephrine, norepinephrine has direct agonist effects on effector cells that contain ›-and œ-receptors. As with other catecholamines, the intracellular action of norepinephrine is mediated via cyclic adenosine monophosphate (cAMP), the production of which is augmented by œ stimulation and attenuated by › stimulation.
The primary pharmacodynamic effects of norepinephrine are cardiac stimulation, particularly at lower doses, and vasoconstriction, which tends to predominate with moderate to higher doses of the drug. Metabolic effects observed with epinephrine, such as glycogenolysis, inhibition of insulin release, and lipolysis, also occur with norepinephrine but are much less pronounced.
The hemodynamic consequences of norepinephrine's cardiovascular stimulation include increases in systolic, diastolic, and pulse pressures. Cardiac output is generally unaffected, although it can be decreased, and total peripheral resistance is also elevated. The elevation in resistance and pressure result in reflex vagal activity, which slows the heart rate and increases stroke volume. The elevation in vascular tone or resistance reduces blood flow to the major abdominal organs as well as to skeletal muscle. As with epinephrine, however, coronary blood flow is substantially increased secondary to the indirect effects of › stimulation. Therefore, unlike epinephrine, norepinephrine does not significantly increase myocardial oxygen consumption, except in patients with variant angina who are hyperresponsive to › stimulation.
Pharmacokinetics: Norepinephrine is ineffective orally, and subcutaneous absorption is poor. As a result, it is recommended that norepinephrine be administered only via the intravenous route. Following IV administration, the onset of activity is rapid, with a short duration of action of only 1-2 minutes following discontinuation of the infusion. The short half-life of norepinephrine is due to the fact that the drug is rapidly inactivated by catechol-O-methyltransferase and monoamine oxidase in the liver and other tissues. The pharmacologic activity of norepinephrine is rapidly terminated by uptake and metabolism in the synaptic cleft. Negligible amounts of norepinephrine are excreted unchanged in urine. Most of the drug is eliminated renally as sulfate-or glucuronide-conjugated metabolites. The drug crosses the placenta but not the blood-brain barrier.
CONTRAINDICATIONS/PRECAUTIONS: Potent vasoconstrictors such as norepinephrine are relatively contraindicated in patients with hypotension secondary to blood volume deficits (hypovolemia).
Norepinephrine is relatively contraindicated in patients with peripheral or mesenteric thrombosis due to the risk of increasing ischemia and extending the area of infarction, unless administration is necessary for a life-saving procedure.
Norepinephrine is relatively contraindicated for use during halothane anesthesia or cyclopropane anesthesia because of the risk of producing ventricular tachycardia or fibrillation. These arrhythmias also can develop in patients with profound hypoxia or hypercarbia.
Norepinephrine is relatively contraindicated in patients with preexisting hyperthyroidism or hypertension it could exacerbate their underlying condition.
DRUG INTERACTIONS: œ-blockers directly antagonize the œ-agonist (i.e., cardiac-stimulating) effects of norepinephrine.
Norepinephrine interacts with halogenated hydrocarbon general anesthetics, such as cyclopropane or halothane, because the anesthetics increase cardiac irritability, which can lead to arrhythmias.
Bretylium can potentiate the action of vasopressors such as norepinephrine on adrenergic receptors, possibly resulting in arrhythmias.
Norepinephrine interacts with guanethidine because guanethidine can increase the pressor response of direct-acting vasopressors, possibly resulting in severe hypertension.
Norepinephrine can cause severe persistent hypertension if administered concurrently with oxytocin.
›-blockers or other drugs with ›-blocking activity, such as phenothiazines, thioxanthines, or haloperidol, directly counteract the vasopressor effects of norepinephrine.
Atropine blocks the vagal reflex bradycardia caused by norepinephrine and increases its pressor effect.
MAOIs, tricyclic antidepressants, ergot alkaloids, and vasopressin, ADH have all been shown to potentiate norepinephrine's pressor action.
The concomitant use of norepinephrine with diuretics can cause decreased arterial responsiveness to vasopressor agents.
Maprotiline when combined with norepinephrine can cause severe cardiovascular effects including arrhythmias, severe hypertension, and/or hyperpyrexia.
ADVERSE REACTIONS: Generalized CNS stimulation can result in adverse effects manifested as fear, anxiety, nervousness, insomnia, excitability, psychomotor agitation, impaired memory, headache, dizziness and disorientation. These reactions can occur with therapeutic doses of systemic norepinephrine. In patients with underlying psychiatric disturbances, norepinephrine can induce more pronounced CNS effects of their pathologic state including panic, hallucinations, aggressive behavior, and expression of suicidal or homicidal tendencies.
Adrenergically modulated vasoactive and smooth muscle responses to norepinephrine can result in nausea/vomiting, diaphoresis, pallor, respiratory weakness, or apnea.
Cardiac arrhythmias, including premature ventricular contractions (PVCs), sinus tachycardia, palpitations, and severe ventricular arrhythmias, are well-described potential adverse effects of norepinephrine due to œ stimulation of the myocardium and conduction system. ECG changes, including ST-T wave changes can occur with or without cardiovascular symptomatology. Angina, dyspnea, pulmonary edema, and ischemia result from the increased workload and subsequent oxygen demands of the adrenergically stimulated heart.
Extravasation of norepinephrine, especially with repeated injections or high infusion rates, can result in severe tissue damage and necrosis. Should extravasation occur, immediate administration of 5-10 mg of phentolamine should be generously infiltrated with a very small gauge needle around the area of extravasation to induce hyperemia and reduce and/or prevent devastating tissue sloughing and necrosis. Caution should be observed to avoid extravasation of norepinephrine, since it can cause tissue necrosis and/or gangrene or other injection site reactions in the surrounding area.
Metabolic acidosis secondary to accumulation of lactic acid has been associated with long-term administration or overdose of norepinephrine.
Hypersensitivity reactions can occur to sulfites contained in norepinephrine injection.
PATIENT INFORMATION:
What does norepinephrine injection do?
Norepinephrine (LevophedTM ) treats a number of serious heart problems including very low blood pressure. Generic norepinephrine injections are not yet available.
What should my doctor, dentist, or pharmacist know before I receive norepinephrine?
They need to know if you have any of the following conditions:
How should I use this medicine?
Norepinephrine is for infusion into a vein. It is given by a health-care professional in a hospital or clinic setting.
What if I miss a dose?
This does not apply.
What other medicines can interact with norepinephrine?
Tell your doctor or pharmacist: about all other medicines you are taking, including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may affect the way your medicine works. Check before starting or stopping any of your medicines.
What side effects may I notice from receiving norepinephrine?
Serious side effects with norepinephrine include:
Call your doctor as soon as you can if you get any of these side effects.
Minor side effects with norepinephrine include:
Let your doctor know about these side effects if they do not go away or if they annoy you.
What do I need to watch for while I receive norepinephrine?
Your condition will be closely monitored during use of norepinephrine.
If you are diabetic norepinephrine may increase your blood sugar. Check your blood or urine sugar often and contact your doctor if you have any problems.
Do not use a norepinephrine solution that appears cloudy, pinkish, brownish, or has a precipitate.
Where can I keep my medicine?
Keep out of the reach of children.
Store at room temperature, approximately 25C (77F). Protect from light. Throw away any unused portion. Do not use if solution is discolored or particles are present. Throw away any unused medicine after the expiration date.
Parkinsn's Archive Treasures Page
John Cottingham is the webmaster of this site.
