Pharmacological treatment of nicotine addiction remains an active area of research. There are many nicotine preparations (nicotine gums, patches, e-cigarettes and inhalational agents) that are freely available in most parts of the world. These products are being heavily promoted and marketed as magical remedies. Nicotine gums are available in 2 mg and 4 mg preparations that deliver around 1 mg and 3 mg nicotine to the blood stream respectively. E-cigarette, a sophisticated nicotine delivery device, delivers nicotine in a vapor form, and it closely mimics the act of smoking. Currently, these products constitute approximately 1% of total nicotine consumption and are showing an increasing trend in most countries.

Nicotine is a dibasic compound and the availability and absorption in human body depends upon the pH of the solution. The absorption can occur through oral mucosa, lungs, skin, or gut. The increase in pH of a solution causes an increase in concentrations of uncharged lipophilic nicotine, in this form it can actively pass through all biological membranes. The addition of slaked lime and catechu to tobacco increases the absorption of nicotine from the oral cavity.

Nicotine, once ingested, is absorbed and metabolized by the liver. The metabolic process can be categorized into two phases. In phase I there is microsomal oxidation of the nicotine via multiple pathways. This leads to formation of various metabolites like cotinine and nornicotine, demethyl cotinine, trans-3-hydroxy-cotinine and d-(3-pyridyl)-g-methylaminobutyric acid. Thereafter, in phase II there is N’-and O’-glucuronidation of the metabolites and excretion via urine, feces, bile, saliva, sweat etc.5-10% of elimination is by renal excretion of unchanged nicotine, however there is reabsorption from the bladder when the urinary pH is high. There is evidence that nitrosation of nicotine in vivo could lead to formation of N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). which are known to be highly carcinogenic. Inflammation in the oral cavity increases risk of endogenous nitrosation.

Nicotine acts via 3 major mechanisms, producing physiological and pathological effects on a variety of organ systems.

- Ganglionic transmission.
- Nicotinic acetylcholine receptors (nAChRs) on chromaffin cells via catecholamines.
- Central nervous system (CNS) stimulation of nAChRs.

Nicotine causes an increased oxidative stress and neuronal apoptosis, DNA damage, reactive oxygen species and lipid peroxide increase. On direct application in humans causes irritation and burning sensation in the mouth and throat, increased salivation, nausea, abdominal pain, vomiting, and diarrhea. Gastrointestinal effects are less severe but can occur even after cutaneous and respiratory exposure. 

Nicotine is one of the most toxic of all poisons and has a rapid onset of action. Apart from local actions, the target organs are the peripheral and central nervous systems. In severe poisoning, there are tremors, prostration, cyanosis, dypnoea, convulsion, progression to collapse and coma. Even death may occur from paralysis of respiratory muscles and/or central respiratory failure with a LD50 in adults of around 30-60 mg of nicotine. In children, the LD50 is around 10 mg.

This is an acute form of nicotine toxicity that is known to occur due to handling of green tobacco leaves, with symptoms lasting from 12 to 24 h. The acute symptoms include headache, nausea, vomiting, giddiness, loss of appetite, fatigue and tachyarrythmias. No significant mortality has been reported due to green tobacco sickness (GTS) but it significantly affects the health of workers in the tobacco industry.

A study relates lung carcinogenesis by nicotine due to genetic variation in CYP2B6. Its simultaneous exposure with hyperoxia has been found to induce cancer in hamsters. Cotinine has been found to promote lung tumorigenesis by inhibiting anti-apoptotic pathway. Nuclear translocation of ARB1 gene by nicotine has found in proliferation and progression of nonsmall-cell lung cancer. Several Studies have shown that nicotine has significant role in tumor progression and metastasis via CXCR4 and increased angiogenesis. Carriers of the lung-cancer-susceptibility loci in their DNA extract more nicotine. Smokers carrying the gene CHRNA3 and CHRNA5 were found to extract more nicotine and cells were thus exposed to a higher internal dose of carcinogenic nicotine-derived nitrosamines. Additionally, modulation of the mitochondrial signaling pathway leads to resistance to the chemotherapeutic agents.

Nicotine use has been associated with Gastro Esophageal Reflux Disorder (GERD) and peptic ulcer disease (PUD). This effect is mediated by increased gastric acid, pepsinogen secretion and stimulatory effects on vasopressin. The action on the cyclo-oxygenase pathway also increases the risk of GERD and PUD. Nicotine causes smooth muscle relaxation by action of endogenous nitric oxide as a nonadrenergic noncholinergic neurotransmitter. The decrease in tone of the colon and gastric motility and reduced lower esophageal sphincteric pressure might be the reason of increased incidence of GERD.

There is an increased incidence of treatment resistant Helicobacter pylori infection in smokers. It potentiates the effects of toxins of H. pylori by its action on the gastric parietal cells. This effect could be due to histamine mediated response of nicotine.

Nicotine has been known to be immunosuppressive through central and peripheral mechanisms. It impairs antigen and receptor mediated signal transduction in the lymphoid system leading to decreased immunological response. The T-cell population is reduced due to arrest of cell cycle. Even the macrophage response, which forms the first line defense against tuberculosis becomes dysfunctional and causes increased incidence of tuberculosis. The migration of fibroblasts and inflammatory cells to the inflamed site is reduced. There is decreased epithelialization and cell adhesion and thus there is a delayed-wound healing as well as increased risk of infection in nicotine exposed individuals.

The action on the hypothalamo-pituitary adrenal axis and autonomic nervous system stimulation via sympathetic and parasympathetic pathways affects the immune system. The adrenocorticotropic hormone (ACTH) secretion pathway and corticotrophin release is affected and this causes immunosuppression.

Nicotine promotes pathologic angiogenesis and retinal neovascularization in murine models. It causes age-related macular degeneration in mice. In a clinical study, the most virulent form of age-related maculopathy was associated with retinal neovascularization that contributed to visual deterioration. Tobacco smokers are known to be at greater risk of age-related macular degeneration than are nonsmokers. 


Nitrous oxide liberated from parasympathetico-nergic nerves plays a pivotal role in generating immediate penile vasodilatation and corpus cavernosum relaxation, and NO derived from endothelial cells contributes to maintaining penile erection. Nicotine causes impairment of NO synthesis. This may lead to loss of penile erections and erectile dysfunction.

Nicotine by inhibiting the 21 hydoxylase causes hypoestrogenic state. It shunts the metabolites to formation of androgen. This leads to chronic anovulation and irregular menstrual cycles. Nicotine can predispose the endometrium to inappropriate cytokine production and irregular bleeding. There is consistent evidence that increase in follicle-stimulating hormone levels and decreases in estrogen and progesterone that are associated with cigarette smoking in women, is at least in part due to the effects of nicotine on the endocrine system.

Maternal smoking has always been known to have deleterious effects on the fetal outcome. There is an increased incidence of intrauterine growth restriction, still birth, miscarriages and mental retardation. 

Maternal as well as grand maternal smoking has been found to increase risk of pediatric asthma. Another serious and important effect is the transgenic transmission of the addictive pattern.

For further information read Mishra A, Chaturvedi P, Datta S, Sinukumar S, Joshi P, Garg A. Harmful effects of nicotine. Indian J Med Paediatr Oncol. 2015 Jan-Mar;36(1):24-31. doi: 10.4103/0971-5851.151771. PMID: 25810571; PMCID: PMC4363846.
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