Nicotinic acid toxicity

Of the water-soluble vitamins, intakes of nicotinic acid [59-67-6] on the order of 10 to 30 times the recommended daily allowance (RE)A) have been shown to cause flushing, headache, nausea, and moderate lowering of semm cholesterol with concurrent increases in semm glucose. Toxic levels of foHc acid [59-30-3] are ca 20 mg/d in infants, and probably approach 400 mg/d in adults. The body seems able to tolerate very large intakes of ascorbic acid [50-81-7] (vitamin C) without iH effect, but levels in excess of 9 g/d have been reported to cause increases in urinary oxaHc acid excretion. Urinary and blood uric acid also rise as a result of high intakes of ascorbic acid, and these factors may increase the tendency for formation of kidney or bladder stones. AH other water-soluble vitamins possess an even wider margin of safety and present no practical problem (82). 

Despite stmctural similarities, the pharmacological consequences of excesses of these substances are quite different. Due to the interest in the effects of nicotinic acid on atherosclerosis, and in particular its use based on its abiUty to lower semm cholesterol, the toxicity of large doses of nicotinic acid has been evaluated. Eor example, in a study designed to assess its abiUty to lower semm cholesterol, only 28% of the patients remained in the study after receiving a large initial dose of 4 g of nicotinic acid due to intolerance at these large doses (70). 

In view of the biological importance of nicotinic acid, it was decided to prepare a quaternary salt from the acid or ester and bromofluoroethane. S Carbethoxy- N-2-fluoroethylpyridinium bromide (XIX) was therefore prepared and examined. The l.d. 50 for subcutaneous injection into mice was 200 mg. /kg., i.e. it was relatively non-toxic compared with methyl fluoroacetate. 

Hepatic Nicotinic acid hepatotoxicity (including cholestatic jaundice) has occurred. Cases of severe hepatic toxicity, including fulminant hepatic necrosis, have occurred in patients who have substituted sustained-release nicotinic acid products for immediate-release nicotinic acid at equivalent doses. Monitor ALT prior to treatment, every 6 to 12 weeks during the first year, and periodically thereafter (approximately 6-month intervals). 

Niacin (nicotinic acid, nicotinamide) has the active forms NAD and NADPH. It functions in electron transfer. A deficiency of niacin causes pellagra, which is characterized by der matitis, diarrhea, and dementia. There is no known toxicity for this vitamin. High doses of niacin are used to treat hyperlipidemia. 

FOOD TOXICANTS, NATURALLY OCCURRING] (Vol 11) Niacm [59-67-6], See also Nicotinic acid. 

Modified-release formulations of nicotinic acid do not appear to be better tolerated than regular formulations, flushing and itching being the most common adverse effects (SEDA-19, 206). There have also been several reports of hepatotoxicity with this form of the drug (SEDA-16,438). Other adverse effects are hepatotoxicity (apparently a dose-related direct toxic effect), hyperglycemia, and hyperuricemia. It has been questioned whether the modified-release formulation, which is available over the counter in some countries, ought to continue to be available for self-medication in view of its serious adverse effects (2,3). 

An apparent interaction between nicotinic acid and alcohol caused toxic delirium and lactic acidosis (45). 

Nicotinic acid undoubtedly provides the basic skeleton for some other alkaloids. Ricinine (Figure 6.35) is a 2-pyridone structure and contains a nitrile grouping, probably formed by dehydration of a nicotinamide derivative. This alkaloid is a toxic constituent of castor oil seeds (Ricinus communis Euphorbiaceae), though the toxicity of the seeds results mainly from the polypeptide ricin (see page 434). Arecoline (Figure 6.36) is found in Betel nuts (Areca catechu Palmae/Arecaceae) and is a tetrahydronicotinic acid derivative. Betel nuts are chewed in India and Asia for the stimulant effect of arecoline. 

Carbohydrate metabolism provides the main energy source in coccidia. Diets deficient in thiamin, riboflavin, or nicotinic acid—all cofactors in carbohydrate metabolism—result in suppression of parasitic infestation of chickens by E tenella and E acervulina. A thiamin analog, amprolium—1-[(4-amino-2-propyl-5-pyrimidinyl)-methyl]-2-picolinium chloride—has long been used as an effective anticoccidial agent in chickens and cattle with relatively low host toxicity. The antiparasitic activity of amprolium is reversible by thiamin and is recognized to involve inhibition of thiamin transport in the parasite. Unfortunately, amprolium has a rather narrow spectrum of antiparasitic activity it has poor activity against toxoplasmosis, a closely related parasitic infection. 

Sources Shrimpton, 1997 Institute of Medicine, 1997, 1998, 2000, 2001 Scientific Committee for Food, 1993 where two figures are shown for vitamin A, the lower is for women and the higher is for men (Table 2.5). for niacin and nicotinic acid, the lower values are for sustained reiease preparations the EU upper level of 25 mg of vitamin Be was proposed by the Scientific Committee for Food Opinion, 2000 and the EU upper level of 200 xg of vitamin B12 was set because of the possible presence of inactive corrinoids in pharmaceutical preparations, not because of toxicity of the vitamin itself. 

Since nicotinic acid can cause unpleasant flushing and other symptoms of vasodilatation, attempts have been made to develop modified-release formulations. Modified-released nicotinic acid formulations may be better tolerated than the immediate-release formulation, because they reduce the vasodilatory effects of the drug. However, the low frequency of flushing produced by modified-release formulations may be offset by an increased risk of hepato-toxicity. Some reports have suggested a higher frequency of hepatic dysfunction with traditional modified-release nicotinic acid formulations compared with immediate-release products (2,39). 

Diarrhea, myalgia/myopathy (watch CK), rhabdomyolysis (T with gemfibrozil and nicotinic acid), T LFTs, possible enhanced toxicity with P450 inhibitors. 

Plants of many genera produce compounds called alkaloids (alkali-like), and indeed all the thousands of known alkaloids contain nitrogen, by definition, and most are basic, and many are also toxic. Nicotine, a structurally simple example of an alkaloid, is a highly toxic substance, and is the major active component in tobacco (Nicotiam sp.), and amongst the most addictive drugs - an extraordinary contrast to the vital role in life played by nicotinic acid amide (32.2.1). Coniine, the active ingredient of hemlock (Conium maculatum), is another stmcturally simple example. 

Nicotinic acid in high doses may affect the cholescintigraphy because of poor extraction and elimination of the radiotracer (toxic effect on hepatocytes). Total parenteral nutrition may cause delayed or no visualization of the gallbladder, even in patients with no gallbladder disease caused by bile stasis and the formation of thick viscous jelly-like bile. Nonvisualization of the gallbladder may also be caused by hepatic artery infusion during chemotherapy. 

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