HOW NICOTINE EFFECTS ON HUMAN HEALTH

Abstract

With the advent of nicotine replacement therapy, the consumption of the nicotine is on the rise. Nicotine is considered to be a safer alternative of tobacco. The IARC monograph has not included nicotine as a carcinogen. However there are various studies which show otherwise. We undertook this review to specifically evaluate the effects of nicotine on the various organ systems. A computer aided search of the Medline and PubMed database was done using a combination of the keywords. All the animal and human studies investigating only the role of nicotine were included. Nicotine poses several health hazards. There is an increased risk of cardiovascular, respiratory, gastrointestinal disorders. There is decreased immune response and it also poses ill impacts on the reproductive health. It affects the cell proliferation, oxidative stress, apoptosis, DNA mutation by various mechanisms which leads to cancer. It also affects the tumor proliferation and metastasis and causes resistance to chemo and radio therapeutic agents. The use of nicotine needs regulation. The sale of nicotine should be under supervision of trained medical personnel.

INTRODUCTION

Tobacco is the leading cause of preventable cancers. WHO estimated around 1.27 billion tobacco users world-wide. Tobacco consumption alone accounts for nearly 5.4 million deaths per year and one billion people may die in this century if global tobacco consumption remained at the current levels. An international treaty spearheaded by WHO in 2003 and signed by 170 countries, aims to encourage governments to reduce the production, sales, distribution advertisement and promotion of tobacco products. Despite strong opposition from the Industry, the treaty has been making steady progress in achieving its goal of comprehensive tobacco control around the world.As tobacco consumption is being curbed, there is a growing demand for cessation. 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 preparation 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 well known to have serious systemic side effects in addition to being highly addictive. It adversely affects the heart, reproductive system, lung, kidney etc. Many studies have consistently demonstrated its carcinogenic potential. The only other known use of nicotine has been as an insecticide since 17^th century.After World War II, its use has declined owing to the availability of cheaper, more potent pesticides that are less harmful to mammals. The environment Protection Agency of United States has banned use of nicotine as a pesticide from 1^stJanuary 2014.India, one of the largest producer and exporter of nicotine sulphate, has progressively banned its use as agricultural pesticide. We undertook this review to evaluate the systemic adverse effects of nicotine.

CHEMICAL PROPERTIES AND METABOLISM

Nicotine was first extracted from tobacco by German physicians Wilhelm Heinrich Posselt and Karl Ludwig Reimann. Nicotine, a strong alkaloid, in its pure form is a clear liquid with a characteristic odour. It turns brown on exposure to air. It is water soluble and separates preferentially from organic solvents. It is an amine composed of pyridine and pyrrolidine rings.

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.

MECHANISM OF ACTION

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

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

Brain imaging studies demonstrate that nicotine acutely increases activity in the prefrontal cortex and visual systems. There is release of a variety of neurotransmitters important in drug-induced reward. Nicotine also causes an increased oxidative stress and neuronal apoptosis, DNA damage, reactive oxygen species and lipid peroxide increase. nAChRs were originally thought to be limited to neuronal cells, however, studies have identified functional nAChRs in tissues outside the nervous system. Actions on nicotinic receptors produce a wide variety of acute and long-term effects on organ systems, cell multiplication and apoptosis, throughout the body.

IMMEDIATE EFFECTS AND TOXICITY

Nicotine 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. Predominant immediate effects as seen in animal studies and in humans consist of increase in pulse rate and blood pressure. Nicotine also causes an increase in plasma free fatty acids, hyperglycemia, and an increase in the level of catecholamines in the blood. There is reduced coronary blood flow but an increased skeletal muscle blood flow.The increased rate of respiration causes hypothermia, a hypercoagulable state, decreases skin temperature, and increases the blood viscosity.

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.

GREEN TOBACCO SICKNESS

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.

NICOTINE ADDICTION

Nicotine is one of the most addicting agent. The US surgeon general (2010) has concluded nicotine to be as addictive as cocaine or heroin. Nicotine interacts with the nicotinic acetyl choline receptors and stimulates the dopaminergic transmission. This in turn stimulates the reward centre and is responsible for the mood elevation and apparent improvement in cognitive function.With chronic stimulation by nicotine the GABAergic neurons are desensitized and thus lose their inhibitory effect on dopamine.This in turn reinforces the addiction by inducing craving. This effect has been shown to affect the CYP2A6 gene and leads to heritable dependence to nicotine. Studies have shown the nicotine dependence to be transmitted maternally and grand maternally by epigenetic mechanism.

EFFECTS ON METABOLISM

Nicotine causes catecholamine release and stimulates the autonomic system. There is increased glycogen synthesis due to α-adrenoceptor stimulation. This leads to reduction in the fasting blood glucose levels. It also causes lipolysis thus decreasing body weight. Nicotine affects insulin resistance and predisposes to metabolic syndrome. In an animal study prenatal exposure was toxic to pancreatic β-cell and leads to decreased B cell population, thus increasing the risk of diabetes.

NICOTINE AND CANCER

The stimulation of nAChRs by nicotine has biologic effects on cells important for initiation and progression of cancer. It activates signal transduction pathways directly through receptor-mediated events, allowing the survival of damaged epithelial cells. In addition, nicotine is a precursor of tobacco specific nitrosamines (TSNAs), through nitrosation in the oral cavity.It is shown that nitrosation of nicotine could lead to formation of NNN and NNK. This effect of nicotine may be important because of its high concentration in tobacco and nicotine replacement products.NNN and NNK are strongly carcinogenic.

Nicotine forms arachidonic acid metabolites which cause increased cell division. Binding to Bcl-2 and action on vascular endothelial growth factor and cyclooxygenase-2 (COX-2) causes increased cancer proliferation and survival.Promotion of tumor angiogenesis accelerates tumor growth which is mediated by β-adrenergic activation and stimulation of nAChRs. Nicotine also suppresses apoptosis by phosphorylation mediated extracellular signal regulated kinases of Bcl-2.Recent studies show that nicotine, activates nuclear factor kappa B (NF-kB)-dependent survival of cancer cell and proliferation.

In normal cells, nicotine can stimulate properties consistent with cell transformation and the early stages of cancer formation, such as increased cell proliferation, decreased cellular dependence on the extracellular matrix for survival, and decreased contact inhibition. Thus, the induced activation of nAChRs in lung and other tissues by nicotine can promote carcinogenesis by causing DNA mutationsThrough its tumor promoter effects, it acts synergistically with other carcinogens from automobile exhausts or wood burning and potentially shorten the induction period of cancers.