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Mechanisms of Flushing Due to Niacin and Abolition of These Effects

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Mechanisms of Flushing Due to Niacin and Abolition of These Effects Review Paper Mechanisms of Flushing Due to Niacin and Abolition of These Effects Aditya Sood, BS; Rohit Arora, MD There are many factors that increase the risk of that has been known to have many pharmaco- cardiovascular disease, and a prominent factor logic uses. When niacin is taken in large doses, it among these is dyslipidemia. The following litera- blocks the breakdown of fats in adipose tissue, ture review focuses on the use of niacin therapy therefore altering the lipid levels of blood. Niacin in order to treat dyslipidemia and how to control may be used in treating hyperlipidemia because it the associated ‘‘niacin flush.’’ The associated lowers very-low-density lipoprotein cholesterol studies gathered are reviews and randomized con- (VLDL-C), which is a precursor of low-density trol trials. They were obtained by using electronic lipoprotein cholesterol (LDL-C), or ‘‘bad’’ choles- searches. Certain keywords took precedence, and terol. Due to its inhibitory effects on breakdown articles focusing on niacin therapy were chosen. of fats, niacin causes a decrease in free fatty acids Recent research has found promising insight into in the blood, therefore decreasing secretion of more effective prevention of the niacin-mediated VLDL-C and cholesterol by the liver. flush through a selective antagonist for the pros- Also, by lowering VLDL-C levels in the blood, taglandin D2 receptor, laropiprant. Aspirin (or niacin increases the level of high-density lipoprotein NSAIDs) also provide some prevention for flush- cholesterol (HDL-C), or ‘‘good’’ cholesterol. There- ing, although recent studies have shown that it is fore, niacin serves a purpose in helping patients with not as effective as laropiprant. There is a need low HDL-C levels who are at high risk for myocar- for further research in order to come to a clear dial infarction. Niacin was the first lipid drug shown conclusion regarding combined therapies of to prevent cardiovascular disease and death in a aspirin and laropiprant pretreatment, as well as large-scale placebo-controlled trial.1 It has mainly exact dosage requirements. J Clin Hypertens been the HDL-C–elevating effects of nicotinic acid 2–4 (Greenwich). 2009;11:685–689. ª2009 Wiley thatrecentlyledtoarenewedinterestinthisdrug. Periodicals, Inc. There are a variety of extended-release formulations of niacin in the market. Statins are the most potent cholesterol-reducing agents available, reducing LDL- iacin, also known as nicotinic acid and vita- C, or ‘‘bad’’ cholesterol by almost 30% to 50%. min B , is a colorless, water-soluble solid N 3 However, they have less of an effect than niacin and fibrates in reducing triglyceride levels and raising From the Chicago Medical School ⁄ North Chicago levels of HDL-C, or ‘‘good’’ cholesterol. When Veterans Affairs, North Chicago, IL niacin therapy was used in combination with sim- Address for correspondence: vastatin (belonging to the class of statins), it reduced Aditya Sood, BS, Chicago Medical School ⁄ North 5 Chicago Veterans Affairs, 3001 Green Bay Road, clinical cardiovascular events by as much as 80%. North Chicago, IL, 60064 E-mail: [email protected] PROBLEMS Manuscript received June 17, 2008; revised September 3, One of the inherent problems with niacin therapy to 2008; accepted November 4, 2008 prevent severe cardiovascular issues due to high doi: 10.1111/j.1559-4572.2008.00050.x cholesterol are the side effects that occur with the VOL. 11 NO. 11 NOVEMBER 2009 THE JOURNAL OF CLINICAL HYPERTENSION 685 pharmacologic doses of niacin administered. Facial immediate-release nicotinic acid.12 Also, the inci- flushing is the most common reported side effect in dence of flushing was shown to decrease further patients. This effect is essentially mediated by prosta- with continued therapy. In a 96-week study using glandin D2 and its effects on dilation of small blood nicotinic acid, 1.9 episodes ⁄patient ⁄month during vessels. The ‘‘niacin flush’’ consists of skin reddening, thefirst4weeksoftreatmenthaddecreasedto itching, and ⁄or burning starting 10 to 20 minutes 0.19 episodes ⁄patient ⁄month by the end of the after oral ingestion of the drugs and lasting about 60 study.7 Niacin is involved in extensive metabolism to 90 minutes.6 This cutaneous vasodilation occurs in via 2 major pathways.13–18 The first pathway is via 70% to 100% of patients in clinical trials and cases, glycine conjugation with niacin to form NUA, and many patients are forced to discontinue the medi- which is responsible for the flushing effect of cation due to the severe flushing of the face and upper niacin. The second pathway involves formation of body.7,8 It is important that these effects are con- nicotinamide adenine dinucleotide, which is respon- trolled in order to allow treatment of such conditions sible for the majority of hepatotoxicity. The mecha- as dyslipidemia. nism behind nicotinic acid action is as follows: There has been much advancement in the pre- Nicotinic acid binds to high-affinity G-protein–cou- ventative methods of flushing with niacin intake. pled receptors expressed in adipose tissue.19–21 The This research study will discuss how some of these G inhibitory–coupled receptor decreases cAMP mechanisms may be used to best control, eliminate, levels and therefore inhibits lipolysis. When this and ⁄or prevent flushing. It is critical to recognize happens, there is a reduced circulating level of non- that flushing is a frequent event with niacin admin- esterified fatty acids, which are precursors istration that can be managed with adequate physi- for hepatic triacylglycerol synthesis and, thus, cian and patient education. VLDL-C.22,23 EFFECT ON RATE OF NIACIN MEDIATION OF NICOTINIC ACID– ADMINISTRATION AND ITS METABOLISM INDUCED FLUSHING In an experiment conducted in 12 healthy males, a As mentioned previously, nicotinic acid–induced dose-escalation study was performed with 2000 mg cutaneous vasodilation, or flushing, is one of the niacin administered at 3 different dosing rates: major problems with the therapeutic use of this slow, intermediate, and fast.9 Plasma and urine drug, as it develops in virtually every patient taking were subsequently analyzed to determine the phar- nicotinic acid. In a few studies, it was determined macokinetics of niacin and its metabolites. It was that nicotinic acid–induced flushing is mediated by found that the maximum plasma concentration and the GPR109 NA receptor and involves the forma- out-of-sample predictive ability for niacin and nico- tion of vasodilatory prostanoids, which mediate not tinuric acid (NUA) increased with the dosing rate, only the short-term metabolic effects but also the suggesting that the amount of niacin absorbed flushing response.24,25 Studies have also pointed to increased, or that clearance of niacin decreased, as epidermal langerhans cells as essential for the cuta- the dosing rate increased.9 Niacin is used both in neous flushing response by nicotinic acid; they the immediate- and extended-release formulations respond to an increase in intracellular calcium con- for treatment of dyslipidemia. The rate of niacin centration due to nicotinic acid, and they express administration is believed to affect the adverse prostanoid synthases required for the formation of event profile, most likely by influencing its meta- vasodilatory prostanoids, including prostaglandin bolic profile.9 It can be interpreted that an increase E2 (PGE2) and prostaglandin D2 (PGD2).2 The in the niacin dosing rate (reflecting a more immedi- calcium increase is the majortriggerforactivation ate release) may lead to an increase in total expo- of phospholipase A2 and the subsequent formation sure to niacin and NUA, although total dose of arachidonic acid, which is further metabolized administered was the same.9 Immediate-release nia- by cyclooxygenase-1 and PGE2 and PGD2 synthas- cin has been associated with cutaneous flushing, es to create the vasodilatory prostanoids. It has whereas sustained-release formulations have been been shown in experiments that depletion of these associated with hepatotoxicity.8,10,11 epidermal langerhans cells but not of macrophages In studies pertaining to niacin extended-release of dendritic cells ablates nicotinic acid–induced tablets, dated 1998, there was one reference to flushing.2 Therefore, from the study mentioned, it ‘‘prolonged-release’’ nicotinic acid reducing the inci- would seem as though epidermal langerhans cells, dence of flushing within the first 2 weeks of treat- besides their immunologic role, are essential media- ment by more than 50%, compared with tors of nicotinic acid–induced flushing or local 686 THE JOURNAL OF CLINICAL HYPERTENSION VOL. 11 NO. 11 NOVEMBER 2009 regulation of blood flow. This is an important find- synthase b chain, niacin decreases hepatic holopar- ing that shows potential for a generation of new ticle high-density lipoprotein catabolism and raises strategies to suppress unwanted effects. HDL-C levels. Niacin also increases redox potential It has also been hypothesized that macrophages in arterial endothelial cells, resulting in the inhibi- are the source of nicotinic acid–induced PGD2 tion of redox-sensitive genes. These recent findings secretions. The epidermal langerhans cells men- may help to better explain the multiple actions of tioned above are similar in morphology and func- niacin.29 tion to macrophages and are also similarly derived from monocytes. Nicotinic acid (0.1–0.3 mmol ⁄L) EVIDENCE FOR USE OF ASA (ASPIRIN) inducedPGD2secretioninculturedhumanmacro- It was determined decades ago that the flushing
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