Nicotinic acid

thumb|class=bg-transparent|Space-filling model of nicotinic acid

Nicotinic acid, or niacin, is an organic compound and a vitamer ofvitamin B₃, an essential human nutrient. It is produced by plants and animals from the amino acid tryptophan.

Nicotinic acid is also a prescription medication. Despite the proven lipid changes, nicotinic acid has not been found useful for decreasing the risk of cardiovascular disease in those already prescribed a statin drug. but a 2017 review incorporating twice as many trials concluded that prescription nicotinic acid, while affecting lipid levels, did not reduce all-cause mortality, cardiovascular mortality, myocardial infarctions, nor fatal or non-fatal strokes. In 2023, it was the 288th most commonly prescribed medication in the US, with more than 500,000 prescriptions.

Nicotinic acid has the formula and belongs to the group of the pyridinecarboxylic acids.

Extra-terrestrial nicotinic acid has been found in carbonaceous chondrite meteorites and in sample-returns from the asteroids 162173 Ryugu and 101955 Bennu.

Definition

The term "niacin" was originally coined from "nicotinic acid vitamin", with the goal of distancing the nutrient B3 from the drug nicotine in tobacco. As a result, it originally referred to the nutritional entity of vitamin B₃. The term "nicotinic acid" unambiguously refers to the substance and the prescription medicine containing it, which treats elevated cholesterol and triglycerides. When used as a drug, daily doses range from 500 to 3,000 mg/day.

Nicotinic acid and nicotinamide are both used for prevention and treatment of pellagra, a disease caused by lack of the vitamin.

As a dietary supplement

In the United States, nicotinic acid is sold as a non-prescription dietary supplement with a range of 100 to 1000 mg per serving. These products often have a Structure/Function health claim allowed by the US Food & Drug Administration (FDA). An example would be "Supports a healthy blood lipid profile." The American Heart Association strongly advises against the substitution of dietary supplement nicotinic acid for prescription nicotinic acid because of potentially serious side effects, which means that nicotinic acid should only be used under the supervision of a health care professional, and because manufacture of dietary supplement nicotinic acid is not as well-regulated by the FDA as prescription nicotinic acid. More than 30 mg nicotinic acid consumed as a dietary supplement can cause skin flushing. Face, arms and chest skin turns a reddish color because of vasodilation of small subcutaneous blood vessels, accompanied by sensations of heat, tingling and itching. These signs and symptoms are typically transient, lasting minutes to hours; they are considered unpleasant rather than toxic. Prescriptions in the US peaked in 2009, at 9.4million Reported side effects include an increased risk of new-onset type 2 diabetes.

Mechanisms

Nicotinic acid reduces synthesis of low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), lipoprotein(a) and triglycerides, and increases high-density lipoprotein cholesterol (HDL-C). The lipid-therapeutic effects of nicotinic acid are partly mediated through the activation of G protein-coupled receptors, including hydroxycarboxylic acid receptor 2 (HCA₂)and hydroxycarboxylic acid receptor 3 (HCA₃), which are highly expressed in body fat. HCA₂ and HCA₃ inhibit cyclic adenosine monophosphate (cAMP) production and thus suppress the release of free fatty acids (FFAs) from body fat, reducing their availability to the liver to synthesize the blood-circulating lipids in question. A decrease in free fatty acids also suppresses liver expression of apolipoprotein C3 and PPARg coactivator-1b, thus increasing VLDL-C turnover and reducing its production. Nicotinic acid also directly inhibits the action of diacylglycerol O-acyltransferase 2 (DGAT2) a key enzyme for triglyceride synthesis. It also inhibits HDL-C hepatic uptake by suppressing production of the cholesterol ester transfer protein (CETP) gene.

Combined with statins

Extended release nicotinic acid was combined with lovastatin (Advicor), and with simvastatin (Simcor), as prescription drug combinations. The combination niacin/lovastatin was approved by the US Food and Drug Administration (FDA) in 2001. The combination niacin/simvastatin was approved by the FDA in 2008. Subsequently, large outcome trials using these nicotinic acid and statin therapies were unable to demonstrate incremental benefit of nicotinic acid beyond statin therapy alone. The FDA withdrew approval of both drugs in 2016. The reason given: "Based on the collective evidence from several large cardiovascular outcome trials, the Agency has concluded that the totality of the scientific evidence no longer supports the conclusion that a drug-induced reduction in triglyceride levels and/or increase in HDL-cholesterol levels in statin-treated patients results in a reduction in the risk of cardiovascular events." The drug company discontinued the drugs.

Contraindications

Prescription immediate release (Niacor) and extended release (Niaspan) nicotinic acid are contraindicated for people with either active or a history of liver disease because both, but especially Niaspan, have been associated with instances of serious, on occasion fatal, liver failure.

Adverse effects

The most common adverse effects of medicinal nicotinic acid () are flushing (e.g., warmth, redness, itching or tingling) of the face, neck and chest, headache, abdominal pain, diarrhea, dyspepsia, nausea, vomiting, rhinitis, pruritus and rash. Flushing was often thought to involve histamine, but histamine has been shown not to be involved in the reaction. Flushing is sometimes accompanied by a prickly or itching sensation, in particular, in areas covered by clothing. Aspirin taken half an hour before the nicotinic acid prevents flushing, as does ibuprofen. Taking nicotinic acid with meals also helps reduce this side effect. Nicotinamide and inositol nicotinate can be used as no-flush forms of vitamin B₃, however the efficacy of the latter is dubious.

Liver damage

Nicotinic acid in medicinal doses can cause modest elevations in serum transaminase and unconjugated bilirubin, both biomarkers of liver injury. The increases usually resolve even when drug intake is continued. Long-term nicotinic acid therapy was also associated with an increase in the risk of new-onset type 2 diabetes.

Other adverse effects

High doses of nicotinic acid can also cause niacin maculopathy, a thickening of the macula and retina, which leads to blurred vision and blindness. This maculopathy is reversible after niacin intake ceases. Niaspan, the slow-release product, has been associated with a reduction in platelet content and a modest increase in prothrombin time.

Nicotinic acid inhibits cytochrome P450 enzymes CYP2E1, CYP2D6 and CYP3A4. Niacin produces a rise in serum unconjugated bilirubin in normal individuals and in those with Gilbert's Syndrome. However, in the Gilbert's Syndrome, the rise in bilirubin is higher and clearance is delayed longer than in normal people. One test used to aid in diagnosing Gilbert's Syndrome involves intravenous administration of nicotinic acid (niacin) in a dose of 50 mg over a period of 30 seconds.

Pharmacokinetics

Both nicotinic acid and nicotinamide are rapidly absorbed from the stomach and small intestine. Absorption is facilitated by sodium-dependent diffusion, and at higher intakes, via passive diffusion. Unlike some other vitamins, the percent absorbed does not decrease with increasing dose, so that even at amounts of 3-4 grams, absorption is nearly complete. NAD converts to NADP by phosphorylation in the presence of the enzyme NAD+ kinase. High energy requirements (brain) or high turnover rate (gut, skin) organs are usually the most susceptible to their deficiency. In the liver, nicotinamide is converted to storage nicotinamide adenine dinucleotide (NAD). As needed, liver NAD is hydrolyzed to nicotinamide and nicotinic acid for transport to tissues, there reconverted to NAD to serve as an enzyme cofactor. For humans, the efficiency of conversion is estimated as requiring 60mg of tryptophan to make 1mg of niacin. Riboflavin, vitamin B₆ and iron are required for the process.

Industrial synthesis

Nicotinic acid was first synthesized in 1867 by oxidative degradation of nicotine with potassium chromate and sulfuric acid Nicotinic acid is prepared by hydrolysis of nicotinonitrile, which, as described above, is generated by oxidation of 3-picoline. Oxidation can be effected by air, but ammoxidation is more efficient. In the latter process, nicotinonitrile is produced by ammoxidation of 3-methylpyridine. Nitrile hydratase is then used to catalyze nicotinonitrile to nicotinamide, which can be sold directly or converted to nicotinic acid. Alternatively, ammonia, acetic acid and paraldehyde are used to make 5-ethyl-2-methyl-pyridine, which is then oxidized to nicotinic acid. New "greener" catalysts are being tested using manganese-substituted aluminophosphates that use acetyl peroxyborate as non-corrosive oxidant, avoiding producing nitrogen oxides as do traditional ammoxidations.

The demand for commercial production includes for animal feed and for food fortification meant for human consumption. According to Ullmann's Encyclopedia of Industrial Chemistry, worldwide 31,000 tons of nicotinamide were sold in 2014.

Climate impact

The production of nicotinic acid creates nitrous oxide as a by-product, which is a potent greenhouse gas. In 2018, it was discovered that a nicotinic acid factory in Visp, Switzerland, was responsible for around one percent of the country's greenhouse gas emissions. Eventually, catalytic scrubbing technology that eliminates most of the emissions was installed in 2021.

Chemistry

This colorless, water-soluble solid is a derivative of pyridine, with a carboxyl group (COOH) at the 3-position.

Prescription nicotinic acid preparations in combination with statin drugs (discontinued) are described above. A combination of niacin and laropiprant had been approved for use in Europe and marketed as Tredaptive. Laropiprant is a prostaglandin D2 binding drug shown to reduce niacin-induced vasodilation and flushing side effects. A clinical trial showed no additional efficacy of Tredaptive in lowering cholesterol when used together with other statin drugs, but did show an increase in other side effects. The study resulted in the withdrawal of Tredaptive from the international market.

History

Niacin as a chemical compound was first described by chemist Hugo Weidel in 1873 in his studies of nicotine, but that predated by many years the concept of food components other than protein, fat and carbohydrates that were essential for life. Vitamin nomenclature was initially alphabetical, with Elmer McCollum calling these fat-soluble A and water-soluble B.

Corn (maize) became a staple food in the southeast United States and in parts of Europe. A disease that was characterized by dermatitis of sunlight-exposed skin was described in Spain in 1735 by Gaspar Casal. He attributed the cause to poor diet. In northern Italy it was named "pellagra" from the Lombard language (agra = holly-like or serum-like; pell = skin). In time, the disease was more closely linked specifically to corn. In the US, Joseph Goldberger was assigned to study pellagra by the Surgeon General of the United States. His studies confirmed a corn-based diet as the culprit, but he did not identify the root cause.

Nicotinic acid was extracted from liver by biochemist Conrad Elvehjem in 1937. He later identified the active ingredient, referring to it as "pellagra-preventing factor" and the "anti-blacktongue factor." It was also referred to as "vitamin PP", "vitamin P-P" and "PP-factor", all derived from the term "pellagra-preventive factor". In the late 1930s, studies by Tom Douglas Spies, Marion Blankenhorn, and Clark Cooper confirmed that nicotinic acid cured pellagra in humans. The prevalence of the disease was greatly reduced as a result. Nicotinic acid was initially synthesized by oxidizing nicotine with potassium chromate and sulfuric acid. The modern explanation is that alkali treatment enhances the bioavailability of tryptophan, not directly for any form of the vitamin.

In 1955, Altschul and colleagues described large amounts of nicotinic acid as having a lipid-lowering property. As such, niacin is the oldest known lipid-lowering drug. Lovastatin, the first 'statin' drug, was first marketed in 1987.

Extra-terrestrial occurrence

Extra-terrestrial nicotinic acid has been found in carbonaceous chondrite meteorites and in sample-returns from the asteroids 162173 Ryugu and 101955 Bennu.

{| class="wikitable"

|+ Vitamin B3 vitamers from extra-terrestrial sources

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! Asteroid !! Nicotinic acid !! Nicotinamide

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| 101955 Bennu