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Levophed

Norepinephrine (INN) or noradrenaline (BAN) is a catecholamine and a phenethylamine with chemical formula C8H11NO3. It is released from the adrenal glands as a hormone into the blood, but it is also a neurotransmitter in the nervous system where it is released from noradrenergic neurons during synaptic transmission. As a stress hormone, it affects parts of the human brain where attention and impulsivity are controlled. more...

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Along with epinephrine, this compound effects the fight-or-flight response, activating the sympathetic nervous system to directly increase heart rate, release energy from fat, and increase muscle readiness.

The host of physiological changes activated by a stressful event are unleashed in part by activation of a nucleus in the brain stem called the locus ceruleus. This nucleus is the origin of most norepinephrine pathways in the brain. Neurons using norepinephrine as their neurotransmitter project bilaterally from the locus ceruleus along distinct pathways to the cerebral cortex, limbic system, and the spinal cord, among other projections.

At synapses it acts on both alpha and beta adrenoreceptors.

Antidepressants

Changes in the norepinephrine system are implicated in depression. Serotonin-norepinephrine reuptake inhibitors (SNRIs) treat depression by increasing the amount of serotonin and norepinephrine available to postsynaptic cells in the brain. There is some recent evidence showing that the norepinephrine transporter also normally transports some dopamine as well, implying that SNRIs may also increase dopamine transmission. This is because SNRIs work by preventing the serotonin and norepinephrine transporter from taking their respective neurotransmitters back to their storage vesicles for later use. If the norepinephrine transporter normally recycles some dopamine too, then SNRIs will also enhance dopaminergic transmission. Therefore, the antidepressant effects associated with increasing norepinephrine levels may also be partly or largely due to the concurrent increase in dopamine (particularly in the prefrontal cortex).

Some other antidepressants (for example some tricyclic antidepressants (TCAs)) affect norepinephrine as well, in some cases without affecting other neurotransmitters (at least not directly).

Role in attention

Norepinephrine, along with dopamine, has come to be recognized as playing a large role in attention and focus. In response, Eli Lilly Pharmaceuticals has released Strattera (atomoxetine), a selective norephinephrine reuptake inhibitor, for the treatment of ADHD in adults and children. Strattera is unique in medications specifically indicated for ADHD, as, unlike the psychostimulants (methylphenidate, dextroamphetamine, Adderall (a racemic mixture of amphetamine salts)), it affects norephinephrine, rather than dopamine. As a result, Strattera has a very low abuse potential and can act 24 hours-per-day. (It should be noted that some antidepressants, including SNRIs, have been used off-label for treatment of ADHD.)

Clinical use

Norepinephrine (commonly referred to by the brand name Levophed) is also a powerful medicine used in critically-ill patients as a vasopressor. It is given intravenously and acts on both alpha-1 and beta-1 adrenergic receptors to cause vasoconstriction. Norepinephrine is mainly used to treat patients in septic shock.

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Propofol and Too Much Sulfite?
From CHEST, 7/1/00 by Jonathan E. Lakamp

To the Editor:

It was with great interest that we read the letter from Dr. Langevin (October 1999) regarding the sulfite content of propofol.[1] Dr. Langevin states that when the generic formulation of propofol (Gensia; Irvine, CA) is given at the maximum labeled dosage of 50 [micro]g/kg/min, the sodium metabisulfite (SMBS) exposure approaches the median lethal dose for rats (125 mg/kg). Assuming that a 70-kg patient receives 50 [micro]g/kg/min of the generic propofol for 24 h, the actual exposure to the patient of SMBS would be a total of 126 mg/d. This dosage of 126 mg/d of SMBS would actually only be 1.8 mg/kg, 70 times less than reported by Dr. Langevin. This level of sulfite exposure would seem to support the conclusion of the US Food and Drug Administration (FDA) that "the substitution of sodium metabisulfite for EDTA [ethylenediaminetetraacetic acid] as an excipient in propofol injection emulsion does not effect the safety profile of the product."[2]

If the total amount of sulfite exposure is of concern, there are several amino acid preparations, utilized in total parenteral nutrition solutions, that provide a much higher level of sulfite. Examples of such products would range from Novamine (Clintec Nutrition; Deerfield, IL), which provides SMBS at approximately 450 mg/d (6.4 mg/kg for a 70-kg patient), to Amionsyn-PF (Abbott; Abbott Park, IL), which provides sodium hydrosulfite at 3,450 mg/d (49 mg/kg for a 70-kg patient).

Dr. Langevin also states that there are only two agents currently being used by anesthesiologists that are sulfite-containing products. In actuality, there are several more sulfite-containing products, including meperidine injection (Elkins-Sinn; Philadelphia, PA), norepinephrine injection (Levophed; Sanofi-Winthrop; New York, NY), and phenylephrine injection (Neo-Synephrine; Sanofi-Winthrop), that are commonly used by anesthesiologists.

The issue of whether SMBS should be used as an excipient in pharmaceutical products is unclear. Until the FDA makes a definitive decision, the actual exposure from replacement products that contain sulfite should be assessed based on appropriate estimations of exposure and compared with currently available products that are being utilized frequently.

Jonathan E. Lakamp, PharmD, BCPS St. Luke's Hosptital Chesterfield, MO

Paul P, Dobesh, PharmD, BCPS St. Louis College of Pharmacy St. Louis, MO

Correspondence to: Jonathan E. Lakamp, PharmD, BCPS, Assistant Director of Pharmacy-Clinical Services, St. Luke's Hospital, Department of Pharmacy, 232 S. Woods Mill Rd, Chesterfield, MO 63017; e-mail: lakaje@stlo.smhs.com

REFERENCES

[1] Langevin PB. Propofol containing sulfite-potential for injury [letter]. Chest 1999; 116:1140-1141

[2] Propofol generic clears FDA with excipient differing from Diprivan. FDC reports: the pink sheets 1999; 61:38

COPYRIGHT 2000 American College of Chest Physicians
COPYRIGHT 2000 Gale Group

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