niacin / nicotinic acid / nicotinamide (vitamin B3)

Introduction

the normal physiological role of nicotinic acid is as a component of the coenzymes NAD and NADP which are essential for oxidation/ reduction reactions in tissue respiration
- recommended daily allowance of niacin is 2–12 mg/day for children, 14 mg/day for women, 16 mg/day for men, and 18 mg/day for pregnant or breast-feeding women
nicotinic acid in pharmacologic doses also lowers serum cholesterol and triglyceride concentrations by inhibiting the synthesis of very low density lipoproteins (VLDL) which are the precursors to the formation of LDL, the principal carrier of blood cholesterol
nicotinamide (“niacinamide”), a metabolite of nicotinic acid, possesses similar function as a vitamin but has no pharmacological value in reducing lipids, nor does it cause vasodilatation
- nicotinamide may be toxic to the liver at doses exceeding 3 g/day for adults
vitamin B3 deficiency may result in the clinical condition pellagra, although mild deficiency may just cause slowing of metabolism and cold intolerance

Pellagra (vitamin B3 deficiency)

aetiology

poor dietary intake
- corn as a stable food - corn is the only grain low in digestible niacin
- tryptophan deficiency
  - tryptophan is an essential amino acid and is converted into niacin
  - tryptophan is found in meat, eggs and nuts
GIT malabsorption
- inflammatory bowel disease (IBD), etc
- chronic alcoholism
- Hartnup disease reduces tryptophan absorption in GIT
increased tryptophan utilisation:
- carcinoid tumour
drugs:
- isoniazid
- chloramphenicol
- mercaptopurine

clinical features

classically, “the four D's”:
- diarrhoea
- dermatitis
- dementia
- death
also:
- photosensitivity
- Casal's necklace lesions on the lower neck
- aggression
- alopecia
- peipheral oedema
- glossitis
- insomnia
- weakness
- confusion
- ataxia
- neuritis
- dilated cardiomyopathy

Actions of pharmacologic doses of nicotinic acid

effect is mostly through its binding to G protein coupled receptors:
- niacin receptor 1 (NIACR1)
  - inhibits cAMP production and thus fat breakdown in adipose tissue and free fatty acids available for liver to produce triglycerides and very-low-density lipoproteins (VLDL) and consequently low-density lipoprotein (LDL)
  - inhibits diacylglycerol acyltransferase-2 (important in hepatic TG synthesis)
- niacin receptor 2 (NIACR2),
involved in both DNA repair
involved in the production of steroid hormones in the adrenal gland
large doses > 35mg/day:
- transient vasodilatation starting 20 minutes after a large dose, and lasts 20-60minutes (possibly prostacyclin mediated)
- may stimulate histamine release resulting in:
  - increased gastric motility and acid production which may activate peptic ulcer
  - exacerbation eczema
  - possibly causing acanthosis nigricans
- may decrease uric acid excretion and precipitate gout
- may impair glucose tolerance
- may exacerbate hepatic dysfunction
very high doses cause toxicity:
- reversible niacin maculopathy
- fulminant liver failure

Actions of pharmacologic doses of nicotinamide

nicotinamide has the same vitamin activity as nicotinic acid, but other pharmacological actions and side effects are different
- unlike nicotinic acid, nicotinamide in doses under 3g/d does not reduce cholesterol, cause GIT upset or cause flushing but it can cause increased sweating, higher blood sugar, lower blood pressure, and increased blood levels of carbamazepine in those taking this medication (very high doses may cause nausea and at doses over 3g/d has potential to cause liver damage)
- it is a NAD+ cellular energy precursor
- it modulates inflammatory cytokines
  - nicotinamide suppressed interleukin (IL)-8 production at the mRNA and protein levels through modulation of the nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) pathways in HaCaT cells and primary keratinocytes stimulated by Propionibacterium acnes, the aetiological agent causing inflammatory acne vulgaris. Nicotinamide downregulated the expression of IL-6, IL-10, monocyte chemoattractant protein-1 and tumor necrosis factor (TNF)-α in UV-irradiated keratinocytes ¹⁾
- it is an inhibitor of the nuclear enzyme poly(adenosine diphosphate-ribose [ADP]) polymerase [PARP], which plays a significant role in DNA repair, maintenance of genomic stability, and cellular response to injury including inflammation and apoptosis
may reduce MASLD
- microRNA-93 (miR-93), which is expressed in the liver, is a key genetic regulator in the development and progression of MASLD
- niacin suppresses miR-93 and thus may reduce MASLD
oral doses of 500mg bd in humans have been shown to:
- reduce solar keratoses by ~20% over 12 months and to reduce incidence of BCCs and SCCs as well as repair UV-mediated skin damage via increasing activity of DNA repair systems
- be of benefit in Rx of acne vulgaris due to its anti-inflammatory, anti-oxidant and sebum effects
oral doses of 500mg tds in humans have been shown to:
- be a useful alternative to systemic steroids in the treatment of bullous pemphigoid when combined with tetracycline. It is less toxic and safer than dapsone and prednisone. ²⁾
topical 1% gels bd have been shown to:
- reduce the mean number of precancerous actinic keratoses by 28% when applied to the head, forearms and hands for six months ³⁾
topical creams or gels using 4-5% nicotinamide on humans have been shown to:
- reduce ageing effects of skin to a similar degree as topical retinoic acid applications ⁴⁾
- be of benefit in Rx of acne rosacea and acne vulgaris ⁵⁾
very high oral doses in rats have been shown to have serious adverse effects:
- when given to developing rats at 1-4g/kg:
  - higher hepatic and renal levels of 8-hydroxy-2'-deoxyguanosine, a marker of DNA damage, and impaired glucose tolerance and insulin sensitivity ⁶⁾
- when given to pregnant rats at 4g/kg:
  - higher fetal death rate, lower fetal weight, reduced in placental and fetal hepatic genomic DNA methylation and genomic uracil contents (a factor modifying DNA for diversity) in the placenta and fetal liver and brain, which could be completely or partially prevented by betaine, and induced tissue-specific alterations in the mRNA expression of the genes encoding nicotinamide N-methyltransferase, DNA methyltransferase 1, catalase and tumour protein p53 in the placenta and fetal liver, and increased fetal hepatic α-fetoprotein mRNA level, which was prevented by betaine supplementation, and thus it may play a role in the development of epigenetic-related diseases in the offspring. ⁷⁾