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Published by anon-561893
Understanding Niacin
Understanding Niacin

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Published by: anon-561893 on May 12, 2007
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iacin, also known as nicotinic acid,was introduced in the mid 1950s asthe first effective lipid-modifyingagent. By inhibiting the mobilization of free fatty acids from peripheral tissues,niacin reduces hepatic synthesis of triglycerides (TG) and the secretion of very low–density lipoprotein (VLDL);niacin may also inhibit the conversion of  VLDL into low-density lipoprotein (LDL).Niacin increases high-density lipoprotein(HDL) cholesterol by blocking hepaticuptake of apolipoprotein A-1, decreasingclearance, and increasing the amount of HDL cholesterol available for reverse cho-lesterol transport.
Niacin is unique inthat it has favorable effects on the com-plete lipoprotein profile. It has beenshown to significantly reduce levels of total cholesterol (TC), LDL cholesterol,and TG. Furthermore, niacin is the onlyavailable agent that significantly lowerslipoprotein (a) and has the greatest HDLcholesterol-raising effects of all availableagents.
In addition, niacin was the firstlipid-altering agent shown to significantlyreduce coronary death and nonfatalmyocardial infarction, as well as total mor-tality, in patients with documented coro-nary heart disease in the Coronary DrugProject (CDP), a large, prospective trial.
Despite the efficacy of niacin in improv-ing lipid profiles and its demonstrated rolein secondary prevention, several factorshave limited its widespread use. The pri-mary limitation of immediate-release (IR)(or plain) niacin is prostaglandin-mediat-ed facial and truncal flushing, which isexperienced by most patients during theinitial days of treatment.
 Although symp-toms diminish over time, many patientsstop therapy before tolerance develops.
Other unwanted effects include itching,mucous membrane irritation, and diar-rhea. Another limitation of niacin IR isthe multiple-dosing requirement (ie, 2 or
Niacin is an important therapeutic option forthe treatment of dyslipidemias and is the onlyagent currently available that favorably affects allcomponents of the lipid profile to a significantdegree. Niacin has consistently been shown to sig-nificantly reduce levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides,and lipoprotein (a), while having the greatest high-density lipoprotein (HDL) cholesterol–raising effectsof all available agents. Niacin has also beenshown to significantly reduce coronary events andtotal mortality. Niacin is available in 3 formula-tions: immediate-release (IR), sustained-release(SR), and a newer formulation, niacin extended-release (ER), all of which differ in their pharmaco-kinetic, efficacy, and safety profiles. Conventionalniacin therapy has notable limitations that includeflushing, most often seen with IR formulations, andhepatotoxicity, associated with SR formulations.These side effects are related to the absorption rateand subsequent metabolism of niacin as deliveredfrom the different products. Niacin ER has a deliv-ery system allowing absorption rates intermediateto that of niacin IR and SR. As a result, niacin ERachieves the efficacy of niacin IR with a reducedincidence of flushing and without the hepaticeffects seen with niacin SR. The pharmacistshould be familiar with the differences amongand the advantages and disadvantages of eachformulation to educate patients and help themachieve the optimal therapeutic benefit of niacinwhile minimizing adverse effects.
(Am J Manag Care 2002;8:S308-S314) 
Understanding NiacinFormulations
 John A. Pieper, PharmD
. . .
. . .
3 times a day).
Niacin IR has beenapproved by the US Food and Drug Administration (FDA) for the treatment of dyslipidemias and is available over thecounter.In an attempt to reduce flushing, sus-tained-release (SR) niacin formulationswere developed in the 1960s. The clinicaluse of some of these products, however,has suggested an increased incidence of hepatotoxicity and gastrointestinal intol-erance.
The studies reviewed in this arti-cle demonstrate that although niacin SR reduces flushing and itching, it has incon-sistent effects on lipoprotein parametersand is associated with an increased risk for various side effects. Sustained-releaseformulations, which are not FDA approvedfor the treatment of dyslipidemia, are usu-ally sold over the counter as health foodsupplements.Niacin extended-release (ER), a recent-ly introduced intermediate-release niacinformulation, has a unique delivery systemthat allows drug absorption over 8 to 12hours. This formulation was developed inan attempt to achieve the lipid-loweringefficacy of niacin IR with a reduced inci-dence of flushing and to minimize thehepatotoxicity seen with longer-acting for-mulations. Niacin ER is FDA approved forthe treatment of dyslipidemia and is avail-able by prescription only.
Pharmacokinetics of Niacin 
 An understanding of the differences inside effect profiles of niacin IR, SR, and ER requires a review of the pharmacokineticsof niacin. Niacin undergoes extensive, sat-urable, first-pass metabolism in the liver,where it is metabolized by 2 hepatic path-ways (
Figure 1
). In one pathway, niacin isconjugated with glycine to form nicotin-uric acid. This conjugative pathway is alow-affinity, high-capacity pathway thatgenerates metabolites that are associatedwith flushing. The second pathway involvesseveral general oxidation-reduction meta-bolic reactions that produce nicotinamideand a series of related products, such asnicotinamide adenine dinucleotide, andultimately several pyrimidinemetabolites.This amidation, or nonconjugative, path-way is a high-affinity, low-capacity path-way with metabolites that are associatedwith hepatotoxicity.
Thus, the absorptionrates of the different formulations dictatethe extent of metabolism by each pathway,the type of metabolites generated, and theside effect profile. Niacin IR is usually com-pletely absorbed within 1 to 2 hours;niacin SR absorption rates vary from prod-uct to product and even batch to batch,but generally exceed 12 hours.
Niacin ER has an absorption rate of 8 to 12 hours.
Niacin IR quickly saturates the amidationpathway, resulting in most of the drugbeing metabolized by the conjugative path-way and thereby causing a high incidenceof flushing. Conversely, niacin SR ismetabolized to a greater extent by the ami-dation pathway, saturating it more slowly. As a result, niacin SR has a lower inci-dence of flushing, but a higher incidence of hepatotoxicity.
Niacin ER, with its inter-mediate dissolution rate, better balancesmetabolism along the 2 pathways, result-ing in a lower rate of flushing and hepaticeffects compared with niacin IR and niacinSR, respectively.The differences in metabolism andrelated side effects can be most clearly
Understanding Niacin Formulations
Figure 1.
The Metabolic Pathways of Niacin
Glycine conjugate(flushing)Amidation pathway(hepatotoxicity)NUA NAM6HN NNO MNA NAD2PY 4PYONCOH
NUA indicates nicotinuric acid; NAM, nicotinamide;6HN, 6-hydroxynicotinamide; NAD, nicotinamide ade-nine dinucleotide; MNA, N-methylnicotinamide; NNO,nicotinamide-N-oxide; 2PY, N-methyl-2-pyridone-5-car-boxamide; 4PY, N-methyl-4-pyridone-5-carboxamide.
Used with permission from Piepho RW. Thepharmacokinetics and pharmacodynamics of agentsproven to raise high-density lipoprotein cholesterol.
Am  J Cardiol.
understood in a simulation model of drugmetabolism after administration of eitherniacin IR or niacin SR. Niacin IR isabsorbed at a rate of approximately 500mg/hour, and, therefore, a 1-g dose of niacin IR would be completely absorbedand metabolized within 2 hours. In con-trast, niacin SR is released at an approxi-mate rate of 50 mg/hour. Therefore,absorption of a 1-g dose of niacin SR would take >20 hours. The rate of metab-olism of the amidation pathway (low capacity, high affinity) is fixed at approxi-mately 40 mg/hour, and once this pathwayis saturated, the remaining niacin must bemetabolized by the higher-capacity,lower-affinity conjugative pathway. Forexample, at 2 hours, niacin IR will gener-ate approximately 80 mg of amidationmetabolites and 920mg of nicotinuricacid, the glycine conjugate of niacin. Incontrast, niacin SR in the same timewould form approximately 80 mg of ami-dation metabolites and 20 mg of theglycine conjugate.This simulation indicates that with theuse of niacin IR, large amounts of nico-tinuric acid (920 mg) are produced andexcreted in the urine, and, as such,niacin IR is likely to produce flushing.However, 12 hours after niacin SR admin-istration,approximately 480 mg of amida-tion metabolites, but only 120 mg of nicotinuric acid, are generated. Followingthe simulation to 24 hours, approximately800 mg of amidation metabolites are gen-erated with niacin SR, along with approxi-mately 200 mg of nicotinuric acid. Theseamounts are in stark contrast to the 80mg of amidation metabolites and 920mg of nicotinuric acid, (~92% of the orig-inal niacin dose) generated with niacinIR over the same time period. Thus,approximately 10 times more amidationmetabolites are excreted when niacin SR is administered, while 4.6 times morenicotinuric acid is excreted with niacin IR versus SR administration. Therefore, theside effects observedwith niacin aredetermined by the absorption rate of niacin from different formulations: flush-ing with niacin IR and hepatotoxicitywith niacin SR.Niacin ER has an absorption rate thatfalls between the values for niacin IR andSR. Theoretically, this intermediate pro-file should lead to the production of lessnicotinuric acid than niacin IR, and there-fore to a lower incidence of flushing, andfewer amidation metabolites than niacinSR, thus minimizing the risk of hepatotox-icity. Using the simulation model describedabove, if 1 g of niacin ER is added to thesimulation at an absorption rate of approx-imately 100 mg/hour, niacin ER would gen-erate 400 mg of amidation metabolitescompared with 800 mg with niacinSR, and600 mg of nicotinuric acid compared to920 mg with niacin IR. Furthermore, thedelivery system of niacin ER makes itsuitable for once-daily dosing at bedtime,which also helps to minimize the flushingside effects by allowing any flushing tooccur while the patient is asleep.
This simulation is supported by limitedexperimental data. In a 1992 crossoverstudy, 10 healthy volunteers received a0.5-g dose of niacin IR and then, after awashout period, a 0.5-g dose of niacin SR.The urinary metabolites of niacin weremeasured and expressed as the mean (±SD) amounts excreted in mg/24 hours. After niacin IR administration, 78 ±14 mgof nicotinuric acid and 171 ±12 mg of 2-pyridone, a major amidation metabolite,were excreted. However, when niacin SR was administered, 19 ±4 mg of nicotinuricacid and 130 ±11 mg of 2-pyridone wereexcreted.
The amount of nicotinuric acidexcreted was 4.1 times more in patientsreceiving niacin IR than niacin SR, where-as the ratio of the amounts of 2-pyridonein the IR group compared with the SR group was 1.3.
Clinical Studies Comparing Niacin Formulations
 Although the absorption profiles andresultant metabolism of niacin from differ-ing formulations help explain the differ-ences in side effect profiles, clinicalstudies that have compared these prod-ucts clarify the actual and relative inci-dence of adverse effects as well as therelative efficacy of niacin formulations.The first published comparative trial

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