General Description
Odorless white crystalline powder with a feebly acid taste. pH (saturated aqueous solution) 2.7. pH (1.3% solution) 3-3.5.
Reactivity Profile
NICOTINIC ACID(59-67-6) is incompatible with strong oxidizers. NICOTINIC ACID(59-67-6) is also incompatible with sodium nitrite.
Air & Water Reactions
Water soluble.
Fire Hazard
Flash point data for this chemical are not available; however, NICOTINIC ACID is probably combustible.
Description
Niacin is an additive to food on the basis of its nutrient supplement qualities as a vitamin (as an enzyme co-factor). This water-soluble vitamin of the B complex occurs in various animal and plant tissues. It is required by the body for the formation of coenzymes NAD and NADP. A deficiency of niacin results in the disease, pellagra.
Physical properties
Nicotinic acid and nicotinamide are colorless crystalline substances. Each is insol uble or only sparingly soluble in organic solvents. Nicotinic acid is slightly soluble
in water and ethanol; nicotinamide is very soluble in water and moderately soluble
in ethanol
Nicotinic acid is amphoteric and forms salts with acids as well as bases. Its car boxyl group can form esters and anhydrides and can be reduced. Both nicotinic acid
and nicotinamide are very stable in dry form, but in solution nicotinamide is hydro lyzed by acids and bases to yield nicotinic ac
The coenzyme forms of niacin are the pyridine nucleotides, NAD(H) and
NADP(H). In each of these compounds, the electron-withdrawing effect of the N-1
atom and the amide group of the oxidized pyridine nucleus enables the pyridine C-4
atom to react with many nucleophilic agents (e.g., sulfite, cyanide, and hydride
ions). It is the reaction with hydride ions (H?) that is the basis of the enzymatic
hydrogen transfer by the pyridine nucleotides; the reaction involves the transfer of
two electrons in a single step
Several substituted pyridines are antagonists of niacin in biological systems:
pyridine-3-sulfonic acid, 3-acetylpyridine, isonicotinic acid hydrazine, 17 and
6-aminonicotinamide
History
Huber first synthesized nicotinic acid in 1867. In 1914, Funk isolated nicotinic acid from rice polishings. Goldberger, in 1915, demonstrated that pellagra is a nutritional deficiency. In 1917, Chittenden and Underhill demonstrated that canine blacktongue is similar to pellagra. In 1935, Warburg and Christian showed that niacinamide is essential in hydrogen transport as diphosphopyridine nucleotide (DPN). In the following year, Euler et al. isolated DPN and determined its structure. In 1937, Elvhehjem et al. cured blacktongue by administration of niacinamide derived from liver. In the same year, Fouts et al. cured pellagra with niacinamide. In 1947, Handley and Bond established conversion of tryptophan to niacin by animal tissues.
Application
Nicotinic acid is a precursor of the coenzymes NAD and NADP. Widely distributed in nature; appreciable amounts are found in liver , fish, yeast and cereal grains. It is a water-soluble b-complex vitamin that is necessary for the growth and health of tissues. Dietary deficiency is associated with pellagra. It was functions as a nutrient and dietary supplement that prevents pellagra. The term "niacin" has also been applied. The term “niacin” has also been applied to nicotinamide or to other derivatives exhibiting the biological activity of nicotinic acid.
Definition
ChEBI: A pyridinemonocarboxylic acid that is pyridine in which the hydrogen at position 3 is replaced by a carboxy group.
Brand name
Niacor (Upsher Smith); Niaspan
(KOS); Nicolar (Sanofi Aventis); Wampocap (Medpointe).
Biological Activity
Nicotinic acid can be converted to nicotinamide in the animal body and, in this form, is found as a component of two oxidation-reduction coenzymes, NAD and NADP.The nicotinamide portion of the coenzyme transfers hydrogens by alternating between an oxidized quaternary nitrogen and a reduced tertiary nitrogen. Enzymes that contain NAD or NADP are usually called dehydrogenases. They participate in many biochemical reactions of lipid, carbohydrate, and protein metabolism. An example of an NAD-requiring system is lactic dehydrogenase which catalyzes the conversion of lactic acid to pyruvic acid.
Biochem/physiol Actions
Nicotinic is an antioxidant and acts as a coenzyme in the form of nicotinamide adenine nucleotides(NAD). It modulates lipid metabolism and may be useful in treating dyslipidemia. Nicotinic acid reduces the low-density lipoprotein (LDL) synthesis and improves high-density lipoprotein (HDL) levels. Deficiency of niacin leads to enhanced lipid peroxidation and is implicated in Crohn′s disease Deficiency also impacts DNA repair and also leads to skin and gastrointestinal disorder pellagra.
Mechanism of action
Nicotinic acid decreases formation and secretion of
VLDL by the liver.This action
appears secondary to its ability to inhibit fatty acid
mobilization from adipose tissue. Circulating free fatty
acids provide the main source of fatty acids for hepatic triglyceride synthesis, and lowering triglyceride synthesis
lowers VLDL formation and secretion by the liver.
Since plasma VLDL is the source of LDL, lowering
VLDL can ultimately lower LDL. In addition, nicotinic
acid shifts LDL particles to larger (more buoyant) sizes.
The larger LDL particles are thought to be less atherogenic.
Nicotinic acid can also significantly increase
plasma HDL levels; the mechanism is unknown.
Pharmacokinetics
Nicotinic acid is readily absorbed. Peripheral vasodilation is seen within 20 minutes, and peak plasma concentrations occur within 45
minutes. The half-life of the compound is approximately one hour, thus necessitating frequent dosing or an extended-release
formulation. Extended release tablets produce peripheral vasodilation within 1 hour, reach peak plasma concentrations within 4 to 5
hours, and have a duration of 8 to 10 hours.
Dosing of nicotinic acid should be titrated to minimize adverse effects. An initial dose of 50 to 100 mg t.i.d. often is used with immediaterelease tablets. The dose then is gradually increased by 50 to 100 mg every 3 to 14 days, up to a maximum of 6 g/day, as tolerated.
Therapeutic monitoring to assess efficacy and prevent toxicity is essential until a stable and effective dose is reached. Similar dosing
escalations are available for extended-release products, with doses normally starting at 500 mg once daily at bedtime..
Clinical Use
Nicotinic acid has been esterified to prolong itshypolipidemic effect. Pentaerythritol tetranicotinate hasbeen more effective experimentally than niacin in reducingcholesterol levels in rabbits. Sorbitol and myo-inositolhexanicotinate polyesters have been used in the treatment ofpatients with atherosclerosis obliterans.The usual maintenance dose of niacin is 3 to 6 g/daygiven in three divided doses. The drug is usually given atmealtimes to reduce the gastric irritation that often accompanieslarge doses.
Side effects
Compliance with nicotinic acid therapy can be poor
because the drug can produce an intense cutaneous
flush. This can be reduced by beginning the drug in
stepped doses of 250 mg twice daily and increasing the
dose monthly by 500 to 1000 mg per day to a maximum
of 3000 mg per day.Taking nicotinic acid on a full stomach
(end of meal) and taking aspirin before dosage can
reduce the severity of flushing. Time-release forms of
nicotinic acid may also decrease cutaneous flushing.
Nicotinic acid can cause gastrointestinal (GI) distress，liver dysfunction (especially at high doses), decreased
glucose tolerance, hyperglycemia, and hyperuricemia.
Thus, it is contraindicated in patients with hepatic dysfunction,
peptic ulcer, hyperuricemia, or diabetes mellitus.
A paradox associated with nicotinic acid is that it is
the most widely available hypolipidemic drug (it is sold
over the counter), yet its use requires the closest management
by the physician.
Synthesis
Nicotinic acid, pyridine-3-carboxylic acid (20.2.9) is synthesized industrially
by heating a paraldehyde trimer of acetaldehyde, under pressure with ammonia,
which leads to the formation of 2-methyl-5-ethylpyridine, followed by oxidation with
nitric acid which gives the desired product.
Metabolism
Nicotinic acid is a B-complex vitamin that is converted to nicotinamide, NAD+
, and NADP+
.The latter two compounds are coenzymes and
are required for oxidation/reduction reactions in a variety of biochemical pathways. Additionally, nicotinic acid is metabolized to a
number of inactive compounds, including nicotinuric acid and N-methylated derivatives. Normal biochemical regulation and feedback
prevent large doses of nicotinic acid from producing excess quantities of NAD+
and NADP+
.Thus, small doses of nicotinic acid, such as
those used for dietary supplementation, will be primarily excreted as metabolites, whereas large doses, such as those used for the
treatment of hyperlipoproteinemia, will be primarily excreted unchanged by the kidney.
Purification Methods
Crystallise the acid from *benzene, EtOH or H2O. It sublimes without decomposition. [McElvain Org Synth Coll Vol I 385 1941, Beilstein 22 III/IV 439, 22/2 V 57.]
