Nicotine and Tobacco
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Nicotine is a highly addictive stimulant found in tobacco. It acts on nicotinic acetylcholine receptors in the brain, releasing dopamine and causing dependence. Long term nicotine use can lead to serious health issues like cancer, cardiovascular disease, and addiction. Treatment involves nicotine replacement therapies, medications like varenicline and bupropion, and behavioral therapies to manage withdrawal symptoms and cravings. Managing nicotine dependence requires a combination of pharmacological and psychological approaches.
Nicotine and Tobacco
- 1. Nicotine and Tobacco Subramani Parasuraman Faculty of Pharmacy AIMST University Malaysia
- 2. Loarning outcome • Upon successful completion of this topic, students should be able to • describe the pharmacological properties of nicotine. • discuss the adverse health effects related with nicotine use.
- 3. Tobacco • Tobacco is the common name of several plants in the genus Nicotiana of the family Solanaceae. More than 70 species of tobacco are known, but the chief commercial crop is Nicotiana tabacum. • Dried tobacco leaves are mainly used for smoking in cigarettes and cigars, as well as pipes and shishas. • They can also be consumed as snuff, chewing tobacco, dipping tobacco, and snus. • Tobacco contains the highly addictive stimulant alkaloid nicotine as well as harmala alkaloids such as harmine, harmaline, and harmalol.
- 4. Nicotine • Nicotine is a stimulatory alkaloid found in tobacco products that is often used for the relief of nicotine withdrawal symptoms and as an aid to smoking cessation. • Nicotine is highly toxic alkaloid. It is the agonist at nicotinic cholinergic receptors.
- 5. Mechanism of action for nicotine • Nicotine acts as an agonist on both NN and NM subtypes of nicotinic cholinergic receptors. Sympathetic as well as parasympathetic ganglia are stimulated, but larger doses cause persistent depolarization and ganglionic blockade.
- 6. Pathways associated with nicotine addiction • Cholinergic system: Nicotine easily enters BBB stimulating nicotinic ACh receptors. Cholinergic receptors are located in several brain segments particularly located in the midbrain tegmentum, the striatum, nucleus accumbens and the ventral tegmentum. • Dopaminergic System: Stimulation of central nicotinic acetylcholine receptors by nicotine results in the release of a variety of neurotransmitters in the brain, most importantly dopamine. Nicotine causes the release of dopamine in the mesolimbic area, the corpus striatum, and the frontal cortex. The release of dopamine in the shell of the nucleus accumbens, as this pathway appears to be critical in drug-induced reward. Ref: Benowitz NL. Annu Rev Pharmacol Toxicol. 2009;49:57-71.
- 7. Psychoactive Effects of Nicotine and Nicotine Withdrawal • In humans, nicotine from tobacco induces stimulation and pleasure, and reduces stress and anxiety. • Smokers come to use nicotine to modulate their level of arousal and for mood control in daily life. Smoking may improve concentration, reaction time, and performance of certain tasks. • When a person stops smoking, nicotine withdrawal symptoms emerge. These include irritability, depressed mood, restlessness, anxiety, problems getting along with friends and family, difficulty concentrating, increased hunger and eating, insomnia, and craving for tobacco. Nicotine withdrawal in untreated smokers produces mood disturbances comparable in intensity to those seen in psychiatric outpatients. Ref: Benowitz NL. Annu Rev Pharmacol Toxicol. 2009;49:57-71.
- 8. Nicotine pharmacokinetics and metabolism • Absorption: Nicotine is a weak base (pKa = 8.0). Absorption through mucous membranes depends on pH. Smoking is a highly efficient form of drug administration, as the drug enters the circulation rapidly through the lungs and moves into the brain within seconds. Inhaled drugs escape first-pass intestinal and hepatic metabolism. The more rapid the rate of absorption and entry of a drug into the brain, the greater the rush, and the more reinforcing the drug. Smoking produces high concentrations of a drug in the brain that are comparable to those seen after intravenous administration. Ref: Benowitz NL. Annu Rev Pharmacol Toxicol. 2009;49:57-71. https://www.healthline.com/health/how-much-nicotine-is-in-a-cigarette The average amount of nicotine in a single cigarette is around 10 to 12 mg.
- 9. Nicotine pharmacokinetics and metabolism • Distribution: After absorption, nicotine enters the bloodstream where, at pH 7.4, it is about 69% ionized and 31% unionized. The peak plasma nicotine concentration during smoking is 10 to 50 ng/mL with about 5 percent being protein-bound. The half-life averages two hours. • The highest affinity for nicotine is in the liver, kidney, spleen, and lung and lowest in adipose tissue. In skeletal muscle, concentrations of nicotine and cotinine are close to that of whole blood. Nicotine binds to brain tissues with high affinity, and the receptor binding capacity is increased in smokers compared with nonsmokers. Ref: Benowitz NL. Annu Rev Pharmacol Toxicol. 2009;49:57-71.; Benowitz NL et al., Handb Exp Pharmacol. 2009;(192):29-60.
- 10. Nicotine pharmacokinetics and metabolism • metabolism: Nicotine is rapidly and extensively metabolized by the liver, primarily by the liver enzyme CYP2A6. Although glucuronidation is usually a minor pathway of nicotine metabolism, in people who have low CYP2A6 activity, glucuronidation can be a major determinant of nicotine clearance. Approx. 80 to 90 percent of nicotine is metabolized by lung, liver, and kidney; the principal metabolite is cotinine, which has a plasma concentration that is 10-fold higher than nicotine. Cotinine has a half-life of 15 to 20 hours and is used as a biomarker of nicotine exposure. The rate of nicotine metabolism is faster in women than men. Ref: Benowitz NL. Annu Rev Pharmacol Toxicol. 2009;49:57-71.
- 11. Nicotine pharmacokinetics and metabolism • Excretion: Nicotine is excreted by glomerular filtration and tubular secretion, with variable reabsorption depending on urinary pH. Approximately 17 percent of nicotine is excreted unchanged in the urine. The rate of urinary excretion is pH-dependent, decreasing in an alkaline urine. Nicotine is found in the milk of lactating women with concentrations that parallel those of plasma. • GENETIC CONSIDERATIONS: Nicotine is metabolized primarily by the liver enzyme cytochrome P450 2A6 (CYP2A6). Genetically slow metabolizers tend to smoke fewer cigarettes per day and are able to quit smoking more easily than fast metabolizers. Ref: Elsa-Grace Giardina. Cardiovascular effects of nicotine. © 2023 UpToDate, Inc. Benowitz NL et al., Handb Exp Pharmacol. 2009;(192):29-60.
- 12. Adverse health effects of nicotine use • Immediate Effects: 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. Nicotine also causes an increase in plasma free fatty acids, hyperglycemia, and an increase in the level of catecholamines in the blood. LD50 in adults of around 30-60 mg of nicotine. In children the LD50 is around 10 mg. Ref: Mishra et al., Indian J Med Paediatr Oncol. 2015 Jan-Mar;36(1):24-31.
- 13. Adverse health effects of nicotine use • 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. • Nicotine Addiction: 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. Ref: Mishra et al., Indian J Med Paediatr Oncol. 2015 Jan-Mar;36(1):24-31.
- 14. Adverse health effects of nicotine use • Effects on Metabolism: Nicotine causes catecholamine release and stimulates the autonomic system. Nicotine increases glycogen synthesis, reduces fasting blood glucose levels, decreasing body weight and affects insulin resistance. Ref: Mishra et al., Indian J Med Paediatr Oncol. 2015 Jan-Mar;36(1):24-31.
- 15. Adverse health effects of nicotine use • Nicotine And Cancer: The stimulation of nicotinic acetylcholine receptor by nicotine has biologic effects on cells and initiates progression of cancer. It activates signal transduction pathways directly through receptor-mediated events, allowing the survival of damaged epithelial cells. • 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. • Nicotine increase the risk of cancer in lungs, gastrointestinal tract, pancreas, breast, Kidney and reproductive system organs. Ref: Mishra et al., Indian J Med Paediatr Oncol. 2015 Jan-Mar;36(1):24-31.
- 16. Nicotine dependence (tobacco addiction) • Nicotine addiction occurs when smokers come to depend on smoking to modulate mood and arousal, relieve withdrawal symptoms, or both. • Symptoms • Can’t stop smoking • Have withdrawal symptoms when try to stop • Keep smoking despite health problems • Give up social activities
- 17. Management of Nicotine dependence • Nicotine replacement therapy (NRT): In NRT, nicotine is given in the form of gum, patches, sprays, inhalers, or lozenges – but not the other harmful chemicals in tobacco. NRT can help relieve some of the physical withdrawal symptoms so that you can focus on the psychological (emotional) aspects of quitting. • Varenicline (Drug therapy): It is used for smoking cessation. Is a partial agonist of the alpha4/beta2 subtype of the nicotinic acetylcholine receptor, that leads to the release of the dopamine in the nucleus accumbens (reward center of the brain) and has the capacity to reduce the feelings of craving and withdrawal caused by smoking cessation. Ref: American Cancer Society
- 18. Management of Nicotine dependence • Bupropion (Drug therapy): It is a weak inhibitor of dopamine and noradrenaline reuptake and antagonise nicotinic acetylcholine receptor function. Bupropion can decrease nicotine withdrawal symptoms (such as irritability, anxiety, restlessness) and urge to smoke. • E-cigarettes: An e-cigarette is an electronic device that delivers nicotine in a vapour. This allows to inhale nicotine without most of the harmful effects of smoking, as the vapour contains no tar or carbon monoxide. Ref: American Cancer Society
- 19. Management of Nicotine dependence • Behavioral Treatments • Cognitive Behavioral Therapy (CBT) • Motivational Interviewing • Mindfulness • Telephone support and quitlines • Text messaging, web-based services, and social media support • Transcranial magnetic stimulation (TMS): TMS is a relatively new approach being tested to treat addiction. It is a physiological intervention that noninvasively stimulates neural activity in targeted areas of the brain using magnetic fields. • Other therapies: • Hypnotherapy • Acupuncture • Aversion therapy • Yoga Ref: NIDA.NIH.GOV | National Institute on Drug Abuse (NIDA) UCSF Health
Editor's Notes
- #12: https://www.uptodate.com/contents/cardiovascular-effects-of-nicotine/print
- #18: https://www.cancer.org/healthy/stay-away-from-tobacco/guide-quitting-smoking/nicotine-replacement-therapy.html
- #20: https://nida.nih.gov/publications/research-reports/tobacco-nicotine-e-cigarettes/what-are-treatments-tobacco-dependence